Pyridinone dicarboxamide for use as bromodomain inhibitors

ABSTRACT

The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy

FIELD OF THE INVENTION

The present invention is directed to certain compounds which arebromodomain inhibitors, processes for their preparation, pharmaceuticalcompositions comprising the compounds and the use of the compounds orthe compositions in the treatment of various diseases or conditions.Compounds which are bromodomain inhibitors may be useful in thetreatment of various diseases and conditions, for example acute orchronic autoimmune and/or inflammatory conditions, viral infections andcancer.

BACKGROUND TO THE INVENTION

The genomes of eukaryotic organisms are highly organised within thenucleus of the cell. The long strands of duplex DNA are wrapped aroundan octomer of histone proteins (most usually comprising two copies ofhistones H2A, H2B, H3 and H4) to form a nucleosome. This basic unit isthen further compressed by the aggregation and folding of nucleosomes toform a highly condensed chromatin structure. A range of different statesof condensation are possible, and the tightness of this structure variesduring the cell cycle, being most compact during the process of celldivision. Chromatin structure plays a critical role in regulating genetranscription, which cannot occur efficiently from highly condensedchromatin. The chromatin structure is controlled by a series of posttranslational modifications to histone proteins, notably histones H3 andH4, and most commonly within the histone tails which extend beyond thecore nucleosome structure. These modifications include acetylation,methylation, phosphorylation, ubiquitinylation, SUMOylation. Theseepigenetic marks are written and erased by specific enzymes, which placethe tags on specific residues within the histone tail, thereby formingan epigenetic code, which is then interpreted by the cell to allow genespecific regulation of chromatin structure and thereby transcription.

Histone acetylation is most usually associated with the activation ofgene transcription, as the modification loosens the interaction of theDNA and the histone octomer by changing the electrostatics. In additionto this physical change, specific proteins recognise and bind toacetylated lysine residues within histones to read the epigenetic code.Bromodomains are small (˜110 amino acid) distinct domains withinproteins that bind to acetylated lysine resides commonly but notexclusively in the context of histones. There is a family of around 50proteins known to contain bromodomains, and they have a range offunctions within the cell.

The BET family of bromodomain containing proteins comprises 4 proteins(BRD2, BRD3, BRD4 and BRDT) which contain tandem bromodomains capable ofbinding to two acetylated lysine residues in close proximity, increasingthe specificity of the interaction. Numbering from the N-terminal end ofeach BET protein the tandem bromodomains are typically labelled BindingDomain 1 (BD1) and Binding Domain 2 (BD2) (Chung et al, J Med. Chem.,2011, 54, 3827-3838).

Chan et al. report that BET bromodomain inhibition suppressestranscriptional responses to cytokine-Jak-STAT signalling in agene-specific maner in human monocytes, which suggests that BETinhibition reduces inflammation partially through suppression ofcytokine activity. (Chan et al., Eur. J. Immunol., 2015, 45: 287-297).

Klein et al. report that the bromodomain protein inhibitor I-BET151suppresses expression of inflammatory genes and matrix degrading enzymesin rheumatoid arthritis synovial fibroblasts, which suggests atherapeutic potential in the targeting of epigenetic reader proteins inrheumatoid arthritis. (Klein et al., Ann. Rheum. Dis., 2014, 0:1-8).

Park-Min et al. report that I-BET151 that targets bromo andextra-terminal (BET) proteins that ‘read’ chromatin states by binding toacetylated histones, strongly suppresses osteoclastogenesis. (Park-Minet al. Nature Communications, 2014, 5, 5418).

Funabashi et al describe 1,2,3,4,-tetrahydroquinolines and conduct aconfiguration and conformation analysis (Funabashi et a, Bulletin of theChemical Society of Japan, 1969, 42, 2885-2894).

WO2014/140076 discloses 2,3-disubstituted1-acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use asbromodomain inhibitors.

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula (I)

and salts thereof;wherein:R¹ is —C₁₋₃alkyl or cyclopropyl;R² is H or —C₀₋₃alkyl-C₃₋₇cycloalkyl, wherein the cycloalkyl group isunsubstituted or substituted with one, two or three R⁵ groups which maybe the same or different;R³ is —H, —C₁₋₄alkyl, cyclopropyl or —(CH₂)_(p)OR¹⁰;R⁴ is a) phenyl (which may be unsubstituted or substituted by one, twoor three R⁷ groups which may be the same or different); b) a 5 or 6membered heteroaryl group (which may be unsubstituted or substituted by—C₁₋₃alkyl, —O—C₁₋₃alkyl or halo); c) a 9 to 11 membered heteroarylgroup (which may be unsubstituted or substituted by one, two or threegroups, which may be the same or different, selected from —C₁₋₃alkyl-R⁸,—OCH₃, —O—C₂₋₃alkyl-R⁸, halo, oxo, —O—CF₃ and —CN); or d)—(CH₂)_(n)-phenyl;p is 1 or 2;n is 1 or 2;R⁵ is halo, phenyl, —C₁₋₆alkyl-R⁸, —CO₂H, —OCH₃, —O—C₂₋₆alkyl-R⁸, —CN,—OH or —NHR⁶;R⁶ is —H, —C(O)OC(CH₃)₃, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, a 4 to 7 memberedheterocyclyl group, or —C₂₋₃alkyl-O—C₁₋₃alkyl wherein the —C₁₋₆alkyl and—C₃₋₇cycloalkyl groups may be optionally substituted by one, two orthree fluoro;R⁷ is —NR¹¹R¹², —C₁₋₃alkyl, halo, —CO₂R¹⁰, —CH₂OH, —CH(R¹¹)OR¹⁰,—C(O)C₁₋₃alkyl, —CH(R¹⁰)NR¹¹R¹², —CN, —CHF₂, —CF₃, —OH, —OCHF₂, —OCF₃,—OCH₃, —O—C₂₋₆alkyl-R⁹, —C₁₋₆alkyl-R⁹ or —O-piperidinyl;R⁸ is —H, —OR¹⁰, —CO₂C(CH₃)₃ or —NR¹¹R¹²;R⁹ is —H, —OR¹⁰ or —NR¹¹R¹²;R¹⁰ is —H or —C₁₋₃alkyl;R¹¹ and R¹² are each independently selected from —H, —C₁₋₃alkyl and—C₁₋₃alkylNR¹³R¹⁴; or R¹¹ and R¹² may join together with the nitrogen towhich they are attached, to form a 4 to 7 membered heterocyclyl groupoptionally substituted by one or two substituents independently selectedfrom —C₁₋₃alkyl, —OH and F; andR¹³ and R¹⁴ are each independently selected from —H, —C₁₋₃alkyl and—C(O)CH₃.

Certain compounds of the invention have been shown to be bromodomaininhibitors, in particular BD2 selective and may be useful in thetreatment of various diseases or conditions, for example acute orchronic auto-immune and/or inflammatory conditions, for examplerheumatoid arthritis and cancer. Accordingly, the invention is furtherdirected to pharmaceutical compositions comprising a compound of formula(I), or a pharmaceutically acceptable salt thereof. The invention isstill further directed to methods of treatment of diseases or conditionsassociated therewith using a compound of formula (I) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. The invention is yet further directed towardsprocesses for the preparation of the compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula (I) and salts thereof are referred to herein as“compounds of the invention”.

“BD2” refers to Binding Domain 2 of any of the the BET family ofproteins BRD2, BRD3, BRD4 or BRDT.

“Alkyl” refers to a saturated hydrocarbon chain having the specifiednumber of carbon atoms. For example, the term “C₁₋₆alkyl” as used hereinrefers to a straight or branched alkyl group having from 1 to 6 carbonatoms, for example 1 to 3 carbon atoms. For example the term “C₀₋₃alkyl”refers to a straight or branched alkyl group having from 0 (i.e. isabsent) to 3 carbon atoms, for example 0 to 2 carbon atoms.Representative branched alkyl groups have one, two or three branches.“Alkyl” includes, but is not limited to, methyl, ethyl, n-propyl,n-butyl, iso-butyl, iso-propyl, t-butyl, pentyl and hexyl.

“Cycloalkyl” refers to a saturated hydrocarbon ring or a saturatedspiro-linked bicyclic hydrocarbon ring, having the specified number ofmember atoms in the ring. For example, the term “C₃₋₇cycloalkyl” as usedherein refers to a cycloakyl group having from 3 to 7 member atoms, forexample 3 member atoms. Examples of C₃₋₇cycloalkyl groups include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and spiro[3.3]heptane.

“Enantiomeric excess” (ee) is the excess of one enantiomer over theother expressed as a percentage. In a racemic modification, since bothenantiomers are present in equal amounts, the enantiomeric excess iszero (0% ee). However, if one enantiomer were enriched such that itconstitutes 95% of the product, then the enantiomeric excess would be90% ee (the amount of the enriched enantiomer, 95%, minus the amount ofthe other enantiomer, 5%).

“Enantiomerically enriched” refers to products whose enantiomeric excess(ee) is greater than zero. For example, “enantiomerically enriched”refers to products whose enantiomeric excess is greater than 50% ee,greater than 75% ee, and greater than 90% ee.

“Enantiomerically pure” as used herein refers to products whoseenantiomeric excess is 99% or greater.

“Half-life” (or “half-lives”) refers to the time required for half of aquantity of a substance to be converted to another chemically distinctspecies in vitro or in vivo.

“Halo” refers to a halogen radical, for example, fluoro, chloro, bromo,or iodo.

“Heteroaryl” refers to a cyclic or bicyclic group having the specifiednumber of member atoms wherein at least a portion of the group isaromatic. The point of attachment to the rest of the molecule may be byany suitable carbon or nitrogen atom. For example, the term “5 or 6membered heteroaryl” as used herein refers to a heteroaryl group having5 or 6 member atoms, including 1 or 2 heteroatoms independently selectedfrom nitrogen, sulphur and oxygen. Examples of “5 or 6 memberedheteroaryl” groups include, but are not limited to, thiophene, pyrazolyland pyridinyl. The term “9 to 11 membered heteroaryl” as used hereinrefers to a bicyclic structure having 9, 10 or 11 member atoms,including 1 or 2 heteroatoms independently selected from nitrogen andoxygen. Examples of “9 to 11 membered heteroaryl” groups include, butare not limited to, 2,3-dihydrobenzo[b][1,4]dioxinyl,1H-benzo[d]imidazolyl, benzoimidazolyl, benzazepinyl,2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, quinoxalinyl, quinolinyl,indazolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, indolinyl, benzofuranyl, isoquinolinyl,and 2,3-dihydrobenzofuranyl.

“Heteroatom” refers to a nitrogen, sulfur, or oxygen atom, for example anitrogen atom or an oxygen atom.

“Heterocyclyl” refers to an aliphatic cyclic group having the specifiednumber of member atoms. The point of attachment may be by any suitablecarbon or nitrogen atom. For example the term “4 to 7 memberedheterocyclyl” as used herein refers to a heterocycle group having 4, 5,6 or 7 member atoms including one nitrogen atom and optionallycontaining a further heteroatom selected from nitrogen, oxygen orsulphur. Examples of “4 to 7 membered heterocycle” groups include, butare not limited to, morpholinyl, piperidinyl, piperazinyl,homopiperazinyl and pyrrolidinyl.

“Member atoms” refers to the atom or atoms that form a chain or ring.Where more than one member atom is present in a chain and within a ring,each member atom is covalently bound to an adjacent member atom in thechain or ring. Atoms that make up a substituent group on a chain or ringare not member atoms in the chain or ring.

“Substituted” in reference to a group indicates that a hydrogen atomattached to a member atom within a group is replaced. It should beunderstood that the term “substituted” includes the implicit provisionthat such substitution be in accordance with the permitted valence ofthe substituted atom and the substituent and that the substitutionresults in a stable compound (i.e. one that does not spontaneouslyundergo transformation such as rearrangement, cyclisation, orelimination). In certain embodiments, a single atom may be substitutedwith more than one substituent as long as such substitution is inaccordance with the permitted valence of the atom. Suitable substituentsare defined herein for each substituted or optionally substituted group.

“Pharmaceutically acceptable” refers to those compounds, materials,compositions, and dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, or otherproblem or complication, commensurate with a reasonable benefit/riskratio.

“Pharmaceutically acceptable excipient” refers to a pharmaceuticallyacceptable material, composition or vehicle involved in giving form orconsistency to the pharmaceutical composition. Each excipient must becompatible with the other ingredients of the pharmaceutical compositionwhen commingled such that interactions which would substantially reducethe efficacy of the compound of formula (I) or a pharmaceuticallyacceptable salt thereof when administered to a patient and interactionswhich would result in pharmaceutical compositions that are notpharmaceutically acceptable are avoided. In addition, each excipientmust of course be pharmaceutically acceptable e.g. of sufficiently highpurity.

“rac” refers to the racemic mixture of the compounds of formula (I). Forexample, “rac-(2S,3R,4R)” means a racemic mixture of the (2S,3R,4R)enantiomer and the (2R,3S,4S) enantiomer.

Throughout the description and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

The compounds of the invention may exist in solid or liquid form. In thesolid state, the compounds of the invention may exist in crystalline ornon-crystalline form, or as a mixture thereof. For compounds of theinvention that are in crystalline form, the skilled artisan willappreciate that pharmaceutically acceptable solvates may be formedwherein solvent molecules are incorporated into the crystalline latticeduring crystallization. Solvates may involve non-aqueous solvents suchas ethanol, iso-propyl alcohol, N,N-dimethylsulfoxide (DMSO), aceticacid, ethanolamine, and ethyl acetate, or they may involve water as thesolvent that is incorporated into the crystalline lattice. Solvateswherein water is the solvent that is incorporated into the crystallinelattice are typically referred to as “hydrates”. Hydrates includestoichiometric hydrates as well as compositions containing variableamounts of water. The invention includes all such solvates.

It will be further appreciated that certain compounds of the inventionthat exist in crystalline form, including the various solvates thereof,may exhibit polymorphism (i.e. the capacity to occur in differentcrystalline structures). These different crystalline forms are typicallyknown as “polymorphs”. The invention includes such polymorphs.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement, and other descriptive properties of thecrystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. It will be appreciatedthat different polymorphs may be produced, for example, by changing oradjusting the reaction conditions or reagents, used in making thecompound. For example, changes in temperature, pressure, or solvent mayresult in polymorphs. In addition, one polymorph may spontaneouslyconvert to another polymorph under certain conditions. Polymorphic formsof compounds of formula (I) may be characterized and differentiatedusing a number of conventional analytical techniques, including, but notlimited to, X-ray powder diffraction (XRPD) patterns, infrared (IR)spectra, Raman spectra, differential scanning calorimetry (DSC),thermogravimetric analysis (TGA) and solid state nuclear magneticresonance (SSNMR).

The compounds according to formula (I) contain one or more asymmetriccentres (also referred to as a chiral centres) and may, therefore, existas individual enantiomers, diastereoisomers, or other stereoisomericforms, or as mixtures thereof. Chiral centres, such as chiral carbonatoms, may also be present in a substituent such as an alkyl group.Where the stereochemistry of a chiral centre present in formula (I), orin any chemical structure illustrated herein, is not specified, thestructure is intended to encompass any stereoisomer and all mixturesthereof. Thus, compounds according to formula (I) containing one or morechiral centres may be used as racemic modifications including racemicmixtures and racemates, enantiomerically-enriched mixtures, or asenantiomerically-pure individual stereoisomers. Accordingly, the presentinvention encompasses all isomers of the compounds of formula (I)whether as individual isomers isolated such as to be substantially freeof the other isomer (i.e. pure) or as mixtures (i.e. racemates andracemic mixtures). An individual isomer isolated such as to besubstantially free of the other isomer (i.e. pure) may be isolated suchthat less than 10%, particularly less than about 1%, for example lessthan about 0.1% of the other isomer is present.

Racemic compounds with a single stereocentre are denoted with either nostereochemistry (single bond) or have the annotation (+/−) or rac.Racemic compounds with two or more stereocentres where relativestereochemistry is known are denoted cis or trans as drawn in thestructure. Resolved single enantiomers with unknown absolutestereochemistry but known relative stereochemistry are referred to with(R* or S*) with the appropriate relative stereochemistry depicted.

Where diastereoisomers are represented and only the relativestereochemistry is referred to, the bold or hashed solid bond symbols (

) are used. Where the absolute stereochemistry is known and the compoundis a single enantiomer, the bold or hashed wedges symbols (

) are used as appropriate.

Individual stereoisomers of a compound according to formula (I) whichcontain one or more asymmetric centres may be resolved by methods knownto those skilled in the art. For example, such resolution may be carriedout (1) by formation of diastereoisomeric salts, complexes or otherderivatives; (2) by selective reaction with a stereoisomer-specificreagent, for example by enzymatic oxidation or reduction; or (3) bygas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support such as silica with a bound chiral ligandor in the presence of a chiral solvent. It will be appreciated thatwhere the desired stereoisomer is converted into another chemical entityby one of the separation procedures described above, a further step isrequired to liberate the desired form. Alternatively, specificstereoisomers may be synthesised by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer to the other by asymmetric transformation.

It will be appreciated that, for compounds of formula (I) tautomers maybe observed. Any comment relating to the biological activity of atautomer should be taken to include both tautomers.

It is to be understood that the references herein to compounds offormula (I) and salts thereof covers the compounds of formula (I) asfree bases, or as salts thereof, for example as pharmaceuticallyacceptable salts thereof. Thus, in one embodiment, the invention isdirected to compounds of formula (I) as the free base. In anotherembodiment, the invention is directed to compounds of formula (I) andsalts thereof. In a further embodiment, the invention is directed tocompounds of formula (I) and pharmaceutically acceptable salts thereof.

Because of their potential use in medicine, salts of the compounds offormula (I) are desirably pharmaceutically acceptable. Suitablepharmaceutically acceptable salts can include acid addition salts orbase addition salts. For a review of suitable pharmaceuticallyacceptable salts see Berge et al., J. Pharm. Sci., 66:1-19, (1977).Typically, a pharmaceutically acceptable salt may be readily prepared byusing a desired acid or base as appropriate. The resultant salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent.

A pharmaceutically acceptable acid addition salt can be formed byreaction of a compound of formula (I) with a suitable inorganic ororganic acid (such as hydrobromic, hydrochloric, sulphuric, nitric,phosphoric, succinic, maleic, acetic, propionic, fumaric, citric,tartaric, lactic, benzoic, salicylic, aspartic, p-toluenesulphonic,benzenesulphonic, methanesulphonic, ethanesulphonic,naphthalenesulphonic such as 2-naphthalenesulphonic, or hexanoic acid),optionally in a suitable solvent such as an organic solvent, to give thesalt which is usually isolated for example by crystallisation andfiltration or by evaporation followed by trituration. A pharmaceuticallyacceptable acid addition salt of a compound of formula (I) can compriseor be for example a hydrobromide, hydrochloride, sulfate, nitrate,phosphate, succinate, maleate, acetate, propionate, fumarate, citrate,tartrate, lactate, benzoate, salicylate, glutamate, aspartate,p-toluenesulphonate, benzenesulphonate, methanesulphonate,ethanesulphonate, naphthalenesulphonate (e.g. 2-naphthalenesulphonate)or hexanoate salt.

Other non-pharmaceutically acceptable salts, e.g. formates, oxalates ortrifluoroacetates, may be used, for example in the isolation of thecompounds of formula (I), and are included within the scope of thisinvention.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the salts of the compounds of formula (I).

It will be appreciated from the foregoing that included within the scopeof the invention are solvates, isomers and polymorphic forms of thecompounds of formula (I) and salts thereof.

STATEMENT OF THE INVENTION

In a first aspect there are provided compounds of formula (I):

and salts thereof;wherein:R¹ is —C₁₋₃alkyl or cyclopropyl;R² is H or —C₀₋₃alkyl-C₃₋₇cycloalkyl, wherein the cycloalkyl group isunsubstituted or substituted with one, two or three R⁵ groups which maybe the same or different;R³ is —H, —C₁₋₄alkyl, cyclopropyl or —(CH₂)_(p)OR¹⁰;R⁴ is a) phenyl (which may be unsubstituted or substituted by one, twoor three R⁷ groups which may be the same or different); b) a 5 or 6membered heteroaryl group (which may be unsubstituted or substituted by—C₁₋₃alkyl, —O—C₁₋₃alkyl or halo); c) a 9 to 11 membered heteroarylgroup (which may be unsubstituted or substituted by one, two or threegroups, which may be the same or different, selected from —C₁₋₃alkylR⁸,—OCH₃, —O—C₂₋₃alkyl-R⁸, halo, oxo, —O—CF₃ and —CN); or d)—(CH₂)_(n)-phenyl;p is 1 or 2;n is 1 or 2;R⁵ is halo, phenyl, —C₁₋₆alkyl-R⁸, —CO₂H, —OCH₃, —O—C₂₋₆alkyl-R⁸, —CN,—OH or —NHR⁶;R⁶ is —H, —C(O)OC(CH₃)₃, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, a 4 to 7 memberedheterocyclyl group, or —C₂₋₃alkyl-O—C₁₋₃alkyl wherein the —C₁₋₆alkyl and—C₃₋₇cycloalkyl groups may be optionally substituted by one, two orthree fluoro;R⁷ is —NR¹¹R¹², —C₁₋₃alkyl, halo, —CO₂R¹⁰, —CH₂OH, —CH(R¹¹)OR¹⁰,—C(O)C₁₋₃alkyl, —CH(R¹⁰)NR¹¹R¹², —CN, —CHF₂, —CF₃, —OH, —OCHF₂, —OCF₃,—OCH₃, —O—C₂₋₆alkyl-R⁹, —C₁₋₆alkyl-R⁹ or —O-piperidinyl;R⁸ is —H, —OR¹⁰, —CO₂C(CH₃)₃ or —NR¹¹R¹²;R⁹ is —H, —OR¹⁰ or —NR¹¹R¹²;R¹⁰ is —H or —C₁₋₃alkyl;R¹¹ and R¹² are each independently selected from —H, —C₁₋₃alkyl and—C₁₋₃alkylNR¹³R¹⁴; or R¹¹ and R¹² may join together with the nitrogen towhich they are attached, to form a 4 to 7 membered heterocyclyl groupoptionally substituted by one or two substituents indecently selectedfrom —C₁₋₃alkyl, —OH and F; andR¹³ and R¹⁴ are each independently selected from —H, —C₁₋₃alkyl and—C(O)CH₃.

In one embodiment there are provided compounds of formula (I) and saltsthereof wherein:

R¹ is —C₁₋₃alkyl or cyclopropyl;

R² is —C₀₋₃alkyl-C₃₋₇cycloalkyl, wherein the cycloalkyl group isunsubstituted or substituted with one, two or three R⁵ groups which maybe the same or different;

R³ is —H, —C₁₋₄alkyl, cyclopropyl or —(CH₂)_(p)OR¹⁰;

R⁴ is a) phenyl (which may be unsubstituted or substituted by one, twoor three R⁷ groups which may be the same or different); b) a 5 or 6membered heteroaryl group (which may be unsubstituted or substituted by—C₁₋₃alkyl, —O—C₁₋₃alkyl or halo); c) a 9 to 11 membered heteroarylgroup (which may be unsubstituted or substituted by one, two or threegroups, which may be the same or different, selected from —C₁₋₃alkylR⁸,—OCH₃, —O—C₂₋₃alkyl-R⁸, halo, oxo, —O—CF₃ and —CN); or d)—(CH₂)_(n)-phenyl;p is 1 or 2;n is 1 or 2;R⁵ is halo, phenyl, —C₁₋₆alkyl-R⁸, —CO₂H, —OCH₃, —O—C₂₋₆alkyl-R⁸, —CN,—OH or —NHR⁶;R⁶ is —H, —C(O)OC(CH₃)₃, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, a 4 to 7 memberedheterocyclyl group, or —C₂₋₃alkyl-O—C₁₋₃alkyl wherein the —C₁₋₆alkyl and—C₃₋₇cycloalkyl groups may be optionally substituted by one, two orthree fluoro;R⁷ is —NR¹¹R¹², —C₁₋₃alkyl, halo, —CO₂R¹⁰, —CH₂OH, —CH(R¹¹)OR¹⁰,—C(O)C₁₋₃alkyl, —CH(R¹⁰)NR¹¹R¹², —CN, —OH, —OCHF₂, —OCF₃, —OCH₃,—O—C₂₋₆alkyl-R⁹, —C₁₋₆alkyl-R⁹ or —O-piperidinyl;R⁸ is —H, —OR¹⁰ or —NR¹¹R¹²;R⁹ is —H, —OR¹⁰ or —NR¹¹R¹²;R¹⁰ is —H or —C₁₋₃alkyl; andR¹¹ and R¹² are each independently selected from —H and —C₁₋₃alkyl; orR¹¹ and R¹² may join together with the nitrogen to which they areattached, to form a 4 to 7 membered heterocyclyl group optionallysubstituted by one or two substituents independently selected from—C₁₋₃alkyl, —OH and F.

In one embodiment there are provided compounds of formula (Ia):

and salts thereof;wherein:R¹ is —C₁₋₃alkyl or cyclopropyl;R² is —C₀₋₃alkyl-C₃₋₇cycloalkyl, wherein the cycloalkyl group isunsubstituted or substituted with 1, 2 or 3 R⁵ groups which may be thesame or different;R³ is —H, —C₁₋₄alkyl or cyclopropyl;R⁴ is a) phenyl (which may be unsubstituted or substituted by 1 or 2 R⁷groups which may be the same or different); or b) a 5 or 6 memberedheteroaryl group (which may be unsubstituted or substituted by methyl ormethoxy); or c) a 9 to 11 membered heteroaryl group (which may beunsubstituted or substituted by 1, 2 or 3 groups, which may be the sameor different, selected from methyl, fluoro and oxo); or d)—(CH₂)_(n)-phenyl;p is 1 or 2;n is 1 or 2;R⁵ is halo, phenyl, —C₁₋₆alkyl-R⁸, —CO₂H, —O—C₁₋₆alkyl-R⁸, —CN, —OH or—NHR⁶;R⁶ is —H or —C(O)OC(CH₃)₃;R⁷ is —NHCH₃, —N(CH₃)₂, —CH₃, —F, —CO₂H, —CH₂OH, —Cl, —C(O)CH₃,—C(O)OCH₃, —CH₂N(CH₃)₂, —CN, —OH, —O—C₁₋₆alkyl-R⁹, —C₁₋₆alkyl-R⁹ or—O-piperidinyl;R⁸ is —H, —OH, —N(CH₃)₂ or —OCH₃;R⁹ is —H, —OH, —N(CH₃)₂ or morpholinyl; andR¹⁰ is —H, methyl or ethyl.

In one embodiment R¹ is methyl, ethyl or cyclopropyl.

In one embodiment R¹ is methyl.

In one embodiment R² is H.

In one embodiment R² is cyclopropyl, cyclobutyl, cyclohexyl,methylcyclobutyl, methycyclopentyl, methylcyclohexyl, ethylcyclopropyl,ethyl cyclohexyl or spiro[3.3]heptanyl, wherein the cyclopropylcyclobutyl, cyclopentyl, and cyclohexyl groups may be unsubstituted orsubstituted with 1 or 2 R⁵ groups which may be the same or different.

In one embodiment R² is cyclopropyl, cyclobutyl, 3-fluorocyclobutyl,3-phenylcyclobutyl, 6-aminosprio[3,3]heptanyl, 2-cyclopropylethyl,(trans)-2-methylcyclopropyl, (trans)-4-hydroxycyclohexyl,2-hydroxymethylcyclopropyl, 2-methoxycyclopropyl, 1-cyanocyclopropyl,2,2-diflourocyclopropyl, 3-(tert)-butoxycarbonylaminocyclobutyl,(1R*,2R*)-2-ethoxycylcpropyl, (1S*,2S*)-2-ethoxycyclopropyl,(trans)-2-ethylcyclopropyl, (1S,2S)-2-hydroxymethylcyclopropyl,(1R,2R)—, 2-hydroxymethylcyclopropyl, (1S,2S)-2-ethylcyclopropyl,(1R,2R)-2-ethylcyclopropyl, (1R,2R)-2-methylcyclopropyl,2-ethoxycyclopropyl, (cis)-4-hydroxycyclohexyl,(1S*,2S*)-2-methoxycyclopropyl, (trans)-2-ethoxycyclopropyl,(cis)-2-methylcyclopropyl, (trans)-2-hydroxymethylcyclopropyl,(trans)-2-ethoxycyclopropyl, (1R*,2R*)-2-methylcyclopropyl,(1R,2R)-2-hydroxymethylcyclopropyl, (1S,2S)-2-methylcyclopropyl,(1S*,2S*)-2-hydroxymethylcyclobutylmethyl, (cis)-3-hydroxycyclobutyl,6-(ter)-butoxycarbonylaminospiro[3.3]heptanyl, 2-phenylcyclobutyl,(cis)-3-hydroxycarbonylcyclobutyl, 1-isobutylcyclopropyl,3-methoxy-2,2-dimethylcyclobutyl, 3-ethoxycyclobutyl,3-methylcyclobutyl, 3-ethoxy-2-methoxycyclobutyl, 1-propylcyclobutyl,(1S,3R)-3-hydroxycyclopenyl, (trans)-2-hydroxycyclohexyl,(cis)-2-hydroxycyclohexyl, 2,2-difluorocyclopropyl, 2-hydroxycyclopenyl,(trans)-2-methoxycyclopropyl, 2-hydroxycyclohexyl,(1R,2S)-2-hydroxycyclopenylmethyl, (cis)-2-hydroxycyclopenylmethyl,(trans)-3-hydroxycyclopenylmethyl, (cis)-3-hydroxycyclopenylmethyl,(trans)-4-hydroxycyclohexyl methyl, (cis)-4-hydroxycyclohexylmethyl,(1R*,2R*)-2-methylcyclopropyl, (1R,3S)-3-hydroxycyclohexylmethyl,(1R,2R)-2-hydroxycyclobutyl, (1S*,3S*)-3-hydroxycyclohexyl,(1R*,3R*)-3-hydroxycyclohexyl, (1S*,3R*)-3-hydroxycyclohexyl,(1R,3S)-3-hydroxycyclohexyl, 2,2-dimethylcyclopropyl,(1S*,2S*)-2-methylcyclopropyl, (trans)-2-methoxycyclobutyl,(1R*)-2,2-dimethylcyclopropyl, or (1S*)-2,2-dimethylcyclopropyl.

In one embodiment R² is cyclopropyl.

In one embodiment R² is (1S,2S)-2-methylcyclopropyl.

In one embodiment R³ is —H, —C₁₋₄alkyl or cyclopropyl.

In one embodiment R³ is H, methyl, ethyl or cyclopropyl.

In one embodiment R³ is H.

In one embodiment R⁴ is a) phenyl (which may be unsubstituted orsubstituted by 1 or 2 R⁷ groups which may be the same or different); b)a 5 or 6 membered heteroaryl (which may be unsubstituted or substitutedby methyl) or c) a 9 to 11 membered heteroaryl (which may beunsubstituted or substituted by methyl).

In one embodiment R⁴ is phenyl, unsubstituted or substituted with 1 or 2R⁷ groups which may be the same or different.

In one embodiment, R⁴ is phenyl, 3-methylaminophenyl,3-dimethylaminophenyl, 3,5-dimethylphenyl, 4-methoxyphenyl,2,3-dimethylphenyl, 2-fluoro-3-methylphenyl, 4-fluoro-3-methylphenyl,4-methoxy-3-methylphenyl, 3-fluoro-5-methylphenyl, 3-methylphenyl,2-fluoro-5-methylphenyl, 3-methoxycarbonylphenyl, 3-hydroxymethylphenyl,3-methoxyphenyl, 3-hydroxyphenyl, 3-(2-hydroxyethoxy)phenyl,3-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 2-fluorophenyl,3-(morpholino)phenyl, 3-chlorophenyl, 3-acetylphenyl, 2-methylphenyl,3-2-(dimethylaminoethoxy)phenyl, 2-fluoro-3-methylphenyl,3-(1-hydroxyethyl)phenyl, 3-hyddroxyphenyl, 2,5-dimethylphenyl,4-methoxycarbonylphenyl, 3-cyanophenyl, 3-(morpholinomethyl)phenyl,3-(dimethylaminomethyl)phenyl, 4-hydroxymethyl, 2-methylphenyl,2-fluoro-5-methyl, 4-fluoro-3-methoxyphenyl,(R*)-3-(1-hydroxyethyl)phenyl, or (S*)-3-(1-hydroxyethyl)phenyl.

In one embodiment R⁴ is 5 or 6 membered heteroaryl, unsubstituted orsubstituted with methyl or methoxy.

In one embodiment R⁴ is:

wherein * denotes the point of attachment to the alkyl residue, andwhich R⁴ may be unsubstituted or substituted by methyl or methoxy.

In one embodiment, R⁴ is 6-methoxypyridin-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 1-methyl-1Hpyrazol-4-yl or6-methylpyridin-2-yl.

In one embodiment R⁴ is a 9 to 11 membered heteroaryl, unsubstituted orsubstituted with methyl.

In one embodiment R⁴ is:

wherein * denotes the point of attachment to the alkyl residue, andwhich R⁴ may be unsubstituted or substituted by methyl.

In one embodiment R⁴ is (2,3-dihydrobenzo[b][1,4]dioxin-5-yl,quinolin-8-yl, 1H-benzo[d]imidazol-4-yl,1-methyl-1H-benzo[d]imidazol-7-yl, quinoxalin-5-yl, 1H-indazol-4-yl,1H-indazol-7-yl, 1H-benzo[d]imidazol-6-yl,2,3,4,5-tetrahydro-1H-benzo[d]ezepin-7-yl,1,2,3,4-tetrahydroquinolin-8-yl, 1H-indol-4-yl, indolin-4-yl,1-methyl-1H-indol-4-yl, 2-methyl-1H-benzo[d]imidazol-4-yl,3-methyl-1H-indol-4-yl, benzofuran-4-yl, isoquinolin-5-yl,1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2,3,4-tetrahydroisoquinolin-8-yl,1,2,3,4-tetrahydroquinolin-5-yl, 1H-indol-3-yl,1-methyl-1H-benzo[d]imidazol-4-yl,4,5,6,7-tetrahydro-H-benzo[d]imidazol-4-yl, benzofuran-3-yl or2,3-dihydrobenzofuran-3-yl.

In one embodiment R⁴ is phenyl, 3-methoxyphenyl, 3-hydroxyethoxyphenylor indolin-4-yl. In another embodiment R⁴ is phenyl. In a furtherembodiment R⁴ is 3-hydroxyethoxyphenyl.

In one embodiment R⁵ is halo, phenyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CO₂H,—C₁₋₆alkyl-OH, —CN, —OH or —NHR⁶. In another embodiment R⁵ is —F,phenyl, methyl, ethyl, n-propyl, —OCH₃, —OCH₂CH₃, —CH₂OH, —CN, —OH, —NH₂or —NHC(O)OC(CH₃)₃. In a further embodiment R⁵ is methyl.

In one embodiment R⁷ is —NHCH₃, —N(CH₃)₂, —CH₃, —OCH₃, —F, —CH₂OH, —CN,—CH₂-morpholinyl, —Cl, —C(O)CH₃, —OCH₂CH₂N(CH₃)₂, —OCH₂CH₂OH, —C(O)OCH₃,—CH₂N(CH₃)₂, —OH, or —CH(CH₃)OH. In another embodiment R⁷ is —NHCH₃,—N(CH₃)₂, —CH₃, —OCH₃, —F, —CH₂OH, —CN, —CH₂-morpholinyl, —Cl, —C(O)CH₃,—OCH₂CH₂N(CH₃)₂, —OCH₂CH₂OH, —C(O)OCH₃, —CH₂N(CH₃)₂, —OH, —CHF₂, —CF₃ or—CH(CH₃)OH. In another embodiment R⁷ is —CH(CH₃)OH.

It is to be understood that the present invention covers allcombinations of substituent groups described hereinabove.

Compounds of the invention include the compounds of Examples 1 to 268and salts thereof.

In a further embodiment there is provided the compounds of Examples 269to 341 and salts thereof.

In a yet further embodiment there is provided the compounds of Examples1 to 341 and salts thereof.

In one embodiment the compound of formula (I) is

-   1-benzyl-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-N5-cyclopropyl-N3-methyl-2-oxo-1-(1-phenylpropyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-N3-methyl-1-(3-(methylamino)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(3-(dimethylamino)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(3-fluorocyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(3,5-dimethylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(4-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-N3-methyl-2-oxo-1-(quinolin-8-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(2,3-dimethylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(2-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(4-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(4-methoxy-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(3-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(2-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N3-methyl-2-oxo-N5-(3-phenylcyclobutyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(6-aminospiro[3.3]heptan-2-yl)-1-benzyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N5-cyclobutyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-cyclobutyl-N3-cyclopropyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-benzo[d]imidazol-4-yl)methyl)-N5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(2-cyclopropylethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   methyl    3-((5-(cyclobutylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate;-   N5-cyclobutyl-1-(3-(hydroxymethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(3-hydroxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-benzo[d]imidazol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (R)—N5-cyclopropyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-((1-methyl-1H-benzo[d]imidazol-7-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N3-methyl-N5-((cis)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((trans)-4-hydroxycyclohexyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-(2-methoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-Cyclopropyl-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-(1-cyanocyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-(quinoxalin-5-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (S*)-1-benzyl-N5-(2,2-difluorocyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   tert-butyl    (3-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclobutyl)carbamate;-   N5-cyclopropyl-1-(4-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(4-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1R*,2R*)-2-ethoxycyclopropyl)-N3-methy-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1S*,2S*)-2-ethoxycyclopropyl)-N3-methy-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-((trans)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(4-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-(quinolin-8-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indazol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indazol-7-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-(4-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(3,5-dimethylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(2-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(2-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(2-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-benzo[d]imidazol-6-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-(3-(morpholinomethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1S,2S)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1S,2S)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-(2-fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   5-bromo-1-((6-methoxypyridin-3-yl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide;-   (+/−)-1-(2-fluoro-5-methylbenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1R,2R)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1S,2S)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-7-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-chlorobenzyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-N3-methyl-1-(3-methylbenzyl)-N5-((1R,2R)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-cyclopropylethyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(6-aminospiro[3.3]heptan-2-yl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(3-fluorocyclobutyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-ethoxycyclopropyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (R)—N5-(3-fluorocyclobutyl)-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (R)—N5-(2-cyclopropylethyl)-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-ethoxycyclopropyl)-N3-methyl-2-oxo-1-((R)-1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1-((R)-1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1-((R)-1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-((2,3,4,5-tetra    hydro-1H-benzo[d]azepin-7-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(2-((cis)-4-hydroxycyclohexyl)ethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(2-((trans)-4-hydroxycyclohexyl)ethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-(4-fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluorobenzyl)-N5-((1S*,2S)-2-methoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluorobenzyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-ethoxycyclopropyl)-1-(4-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-N5-cyclopropyl-N3-methyl-2-oxo-1-(1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(3-fluorocyclobutyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-cyclopropylethyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-N5-(2-ethoxycyclopropyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-N5-(2-(hydroxymethyl)cyclopropyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(6-aminospiro[3.3]heptan-2-yl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-1-(3-methoxybenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-acetyl    benzyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-N5-cyclopropyl-N3-methyl-2-oxo-1-(1-(o-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluoro-3-methylbenzyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-ethoxycyclopropyl)-1-(4-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-((1,2,3,4-tetrahydroquinolin-8-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-(3-fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N3-methyl-N5-((1R,2R)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluoro-3-methylbenzyl)-N3-methyl-N5-(2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(3-(2-(dimethylamino)ethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(((+/−)-trans)-2-ethoxycyclopropyl)-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-((1H-indol-4-yl)methyl)-N5-((trans)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(3-fluorocyclobutyl)-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-cyclopropylethyl)-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-N5-(2-ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-1-(3-(2-hydroxyethoxy)benzyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(6-aminospiro[3.3]heptan-2-yl)-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   rac-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (R*)—N5-cyclopropyl-N3-methyl-2-oxo-1-(1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-ethoxycyclopropyl)-1-(2-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-cyclopropylethyl)-1-(2-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(2-ethoxycyclopropyl)-1-(2-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluoro-3-methylbenzyl)-N5-(3-fluorocyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-(6-aminospiro[3.3]heptan-2-yl)-1-(2-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluorobenzyl)-N5-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluorobenzyl)-N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluorobenzyl)-N3-methyl-N5-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluorobenzyl)-N3-methyl-N5-((1S*,2S))-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1R*,2R*)-2-ethoxycyclopropyl)-1-(4-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1S*,2S*)-2-ethoxycyclopropyl)-1-(4-fluorobenzyl)-N3-methy-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1R*,2R*)-2-ethoxycyclopropyl)-1-(4-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1S*,2S*)-2-ethoxycyclopropyl)-1-(4-fluoro-3-methylbenzyl)-N3-methy-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1R*,2R*)-2-ethoxycyclopropyl)-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1S*,2S*)-2-ethoxycyclopropyl)-1-(3-fluorobenzyl)-N3-methy-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-((1,2,3,4-tetrahydroisoquinolin-5-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluoro-5-methylbenzyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N5-((trans)-2-(hydroxymethyl)cyclopropyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluorobenzyl)-N3-methyl-N5-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluorobenzyl)-N3-methyl-N5-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N5-(3-fluorocyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N5-(2-cyclopropylethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-((1H-indol-4-yl)methyl)-N5-(2-ethoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-((1H-indol-4-yl)methyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-((1H-indol-4-yl)methyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N3-methyl-1-(3-methylbenzyl)-N5-((cis)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N5-cyclopropyl-1-(3-(1-hydroxyethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1R,2R)-2-(hydroxymethyl)cyclopropyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(indolin-4-ylmethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-((1-methyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-((2-methyl-1H-benzo[d]imidazol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-methoxybenzyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-((3-methyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indazol-7-yl)methyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N5-((trans)-2-ethylcyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(benzofuran-4-ylmethyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((trans)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1-((S*)-1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-(1-(1H-indol-4-yl)ethyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N5-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-methoxybenzyl)-N3-methyl-N5-((1R,2R)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(cyclopropyl(phenyl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(cyclobutylmethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-N3-methyl-2-oxo-1-(pyridin-4-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-N3-methyl-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-N3-methyl-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(2-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-N3-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-1-(2,5-dimethylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((cis)-3-hydroxycyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(3,3-difluorocyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   tert-cutyl    (6-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)spiro[3.3]heptan-2-yl)carbamate;-   1-cenzyl-N3-methyl-2-oxo-N5-(2-phenylcyclobutyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (cis)-3-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclobutanecarboxylic    acid;-   N5-cyclobutyl-1-(isoquinolin-5-ylmethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (S*)—N5-cyclobutyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-cyclobutyl-N3-ethyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(1-isobutylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(3-methoxy-2,2-dimethylcyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(3-ethoxycyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N3-methyl-N5-(3-methylcyclobutyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(3-ethoxy-2-methoxycyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N3-methyl-2-oxo-N5-(1-propylcyclopropyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (S*)—N5-cyclopropyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   methyl    4-((5-(cyclobutylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate;-   1-benzyl-N5-(2-ethoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclobutyl-N3-methyl-2-oxo-1-(quinolin-5-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1S,3R)-3-hydroxycyclopentyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-cyanobenzyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-((trans)-2-hydroxycyclohexyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-((cis)-2-hydroxycyclohexyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-((6-methylpyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (R*)-1-benzyl-N5-(2,2-difluorocyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-(2-hydroxycyclopentyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-(3-phenylpropyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-phenethyl-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-(3-(morpholinomethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-(2-fluorobenzyl)-N3-methyl-N5-((cis)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-(2-fluorobenzyl)-N5-((trans)-2-methoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((2-hydroxycyclohexyl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-(((1R,2S)-2-hydroxycyclopentyl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-(((cis)-2-hydroxycyclopentyl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-(((trans)-3-hydroxycyclopentyl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-(((cis)-3-hydroxycyclopentyl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(((trans)-4-hydroxycyclohexyl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(((cis)-4-hydroxycyclohexyl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   methyl    4-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate;-   N5-cyclopropyl-1-(3-((dimethylamino)methyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluorobenzyl)-N5-((1R*,2R*)-2-methoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (R)—N5-(6-aminospiro[3.3]heptan-2-yl)-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-(((1R,3S)-3-hydroxycyclohexyl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(4-methoxy-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N5-((cis)-2-ethoxycyclopropyl)-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1R,2R)-2-hydroxycyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(4-(hydroxymethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (S*)—N5-cyclopropyl-N3-methyl-2-oxo-1-(1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (S*)—N5-cyclopropyl-N3-methyl-2-oxo-1-(1-(o-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (R*)—N5-cyclopropyl-N3-methyl-2-oxo-1-(1-(o-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluoro-3-methylbenzyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-(2-fluoro-3-methylbenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1S*,3S*)-3-hydroxycyclohexyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(1R*,3R*)-3-hydroxycyclohexyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(1S*,3R*)-3-hydroxycyclohexyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-((1R,3S)-3-hydroxycyclohexyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-((1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N5-(6-aminospiro[3.3]heptan-2-yl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N5-((cis)-2-ethoxycyclopropyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N5-((trans)-2-ethoxycyclopropyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N5-(2,2-dimethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluorobenzyl)-N5-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluorobenzyl)-N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N3-methy-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(3-fluoro-5-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-((1,2,3,4-tetrahydroquinolin-5-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluoro-5-methylbenzyl)-N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(2-fluoro-5-methylbenzyl)-N5-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1S*,2S′*)-2-(hydroxymethyl)cyclopropyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1S*,2S*)-2-ethoxycyclopropyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1S*,2S*)-2-ethoxycyclopropyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluoro-3-methylbenzyl)-N5-((1R*,2R)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluoro-3-methylbenzyl)-N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-fluorobenzyl)-N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-fluorobenzyl)-N5-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N5-((trans)-2-ethoxycyclopropyl)-1-(2-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(4-fluoro-3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-3-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-fluorobenzyl)-N3-methyl-N5-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-fluorobenzyl)-N3-methyl-N5-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N5-((trans)-2-methoxycyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(2-hydroxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-1-((1-methyl-1H-benzo[d]imidazol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(3-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-1-(3-(morpholinomethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (R*)-1-benzyl-N5-(2,2-dimethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (S*)-1-benzyl-N5-(2,2-dimethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-N3-methyl-2-oxo-1-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N3-methyl-1-(3-methylbenzyl)-N5-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N3-methyl-1-(3-methylbenzyl)-N5-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1R*,2R*)-2-ethoxycyclopropyl)-1-(2-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1S*,2S*)-2-ethoxycyclopropyl)-1-(2-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1R*,2R*)-2-ethoxycyclopropyl)-1-(2-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1S*,2S*)-2-ethoxycyclopropyl)-1-(2-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluoro-3-methylbenzyl)-N3-methyl-N5-((1R*2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(4-fluoro-3-methylbenzyl)-N3-methyl-N5-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N3-methyl-N5-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1-((R)-1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N3-methyl-N5-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1-((R)-1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(1-(3-methoxyphenyl)ethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-(3-(2-hydroxyethoxy)benzyl)-N5-((trans)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(benzofuran-3-ylmethyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N5-((trans)-2-ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (R*)—N5-cyclopropyl-1-(3-(1-hydroxyethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (S*)—N5-cyclopropyl-1-(3-(1-hydroxyethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((trans)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1-((S*)-1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide;    or-   N5-cyclopropyl-1-((2,3-dihydrobenzofuran-3-yl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N³-methyl-N⁵-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N³-methyl-N⁵-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-pyrrolo[3,2-c]pyridin-4-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-cyclopropyl-N³-methyl-1-((2-methyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-(difluoromethoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-cyclopropyl-1-(3-(difluoromethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-cyclopropyl-N³-methyl-2-oxo-1-(quinolin-7-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((S*)-1-(3-methoxyphenyl)ethyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-(2-hydroxyethoxy)benzyl)-N⁵-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-(2-hydroxyethoxy)benzyl)-N⁵-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-((1R*,2R*)-2-ethylcyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-((1S*,2S*)-2-ethylcyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-((1R*,2R*)-2-ethoxycyclopropyl)-1-(3-(2-hydroxyeth    oxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-((1S*,2S*)-2-ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-(2-((trans)-4-aminocyclohexyl)ethyl)-1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-(2-((cis)-4-aminocyclohexyl)ethyl)-1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-pyrrolo[3,2-c]pyridin-4-yl)methyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (±)-1-benzyl-N⁵-((trans)-2-(methoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-cyclopropyl-1-(3-(2-hydroxyethyl)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-tert-butyl    2-((trans)-2-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclopropyl)acetate;-   N⁵-cyclopropyl-N³-methyl-1-(3-(2-morpholinoethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   3-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoic    acid;-   1-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-cyclopropyl-1-(3-(2-(dimethylamino)ethyl)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(indolin-4-ylmethyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N⁵-((1S,2S)-2-(methoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N⁵-((trans)-2-ethylcyclopropyl)-1-(indolin-4-ylmethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-(2-hydroxyethyl)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N⁵-((1S,2R)-2-((dimethylamino)methyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-((6-methyl    pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N⁵-((trans)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-cyclopropyl-1-((1-(2-hydroxyethyl)-1H-indol-3-yl)methyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-(3-(2-morpholinoethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N⁵-((1R,2R)-2-(methoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N⁵-((1R,2R)-2-(ethoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-hydroxybenzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N⁵-((1S,2S)-2-(ethoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-(2-methoxyethoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-((S)-2-hydroxypropoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-(3-(2-morpholinoethoxy)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3-((R)-2-hydroxypropoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-((1H-indol-4-yl)methyl)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N⁵-((1S*,2R*)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N⁵-((1R*,2S*)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-((1H-indol-4-yl)methyl)-N⁵-((trans)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N³-ethyl-1-(indolin-4-yl    methyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-N³-ethyl-1-(3-(2-hydroxyethoxy)benzyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-((1H-indol-4-yl)methyl)-N⁵-((trans)-2-(2-((2-aminoethyl)(methyl)amino)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N⁵-(trans-3-hydroxycyclobutyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-cyclopropyl-N³-methyl-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-((1H-indol-4-yl)methyl)-N⁵-((trans)-2-(2-((2-acetamidoethyl)(methyl)amino)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N³-methyl-N⁵-((1R*,2R*)-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N³-methyl-N⁵-((1S*,2S*)-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N³-methyl-N⁵-((trans)-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (R*)—N⁵-cyclopropyl-1-(2-hydroxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (S*)—N⁵-cyclopropyl-1-(2-hydroxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (S*)—N⁵-cyclopropyl-1-(2-methoxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N⁵-cyclopropyl-N³-methyl-1-((2-methylbenzo[d]oxazol-7-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((R*)-1-(3-methoxyphenyl)ethyl)-N³-methyl-N⁵-(1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   (+/−)-1-benzyl-N⁵-((trans)-2-((dimethylamino)methyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((6-methoxypyridin-2-yl)methyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1-(1-(pyridin-2-yl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((4-methoxypyridin-2-yl)methyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-((4-methylpyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N⁵-((1R,2S)-2-((dimethylamino)methyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-(3,5-dimethoxybenzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   methyl    4-((3-(methylcarbamoyl)-5-(((1S,2S)-2-methylcyclopropyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate;-   4-((3-(methylcarbamoyl)-5-(((1S,2S)-2-methylcyclopropyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoic    acid;-   1-(4-(2-aminoethoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;    and-   1-benzyl-N⁵-((trans)-3-hydroxycyclobutyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide    or a salt thereof.

In one embodiment, the compound of formula (I) is:

-   1-benzyl-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-benzyl-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-((1R,2R)-2-(hydroxymethyl)cyclopropyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   N5-cyclopropyl-1-(indolin-4-ylmethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;    or-   1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   or a salt thereof.

In one embodiment the compound of formula (I) is:

-   1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   1-((1H-indol-4-yl)methyl)-N³-methyl-N⁵-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;    or-   1-((1H-pyrrolo[3,2-c]pyridin-4-yl)methyl)-N³-methyl-N-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide;-   or a salt thereof.

In one embodiment the compound of formula (I) is1-benzyl-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideor a salt thereof. In another embodiment the compound of formula (I) is1-benzyl-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideor a pharmaceutically acceptable salt thereof. In a further embodimentthe compound of formula (I) is1-benzyl-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide.

In one embodiment the compound of formula (I) is

or a salt thereof.

In another embodiment the compound of formula (I) is a pharmaceuticallyacceptable salt of

In a further embodiment the compound of formula (I) is

In one embodiment the compound of formula (I) is1-benzyl-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideor a salt thereof. In another embodiment the compound of formula (I) is1-benzyl-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideor a pharmaceutically acceptable salt thereof. In a further embodimentthe compound of formula (I) is1-benzyl-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide.

In one embodiment the compound of formula (I) is

or a salt thereof.

In another embodiment the compound of formula (I) is a pharmaceuticallyacceptable salt of

In a further embodiment the compound of formula (I) is

In one embodiment the compound of formula (I) is

or a salt thereof.

In another embodiment the compound of formula (I) is a pharmaceuticallyacceptable salt of

In a further embodiment the compound of formula (I) is

In one embodiment, the compound of formula (I) is1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideor a salt thereof. In another embodiment, the compound of formula (I) is1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideor a pharmaceutically acceptable salt thereof. In a further embodiment,the compound of formula (I) is1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide.

In one embodiment the compound of formula (I) is

or a salt thereof.

In another embodiment the compound of formula (I) is a pharmaceuticallyacceptable salt of

In a further embodiment the compound of formula (I) is

In one embodiment the compound of formula (I) is

or a salt thereof.

In another embodiment the compound of formula (I) is a pharmaceuticallyacceptable salt of

In a further embodiment the compound of formula (I) is

In a second aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.

In a third aspect of the present invention, there is provided a compoundof formula (I), or a pharmaceutically acceptable salt thereof for use intherapy, in particular in the treatment of diseases or conditions forwhich a bromodomain inhibitor is indicated.

In a fourth aspect of the present invention, there is provided a methodof treating diseases or conditions for which a bromodomain inhibitor isindicated in a subject in need thereof which comprises administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In a fifth aspect of the present invention, there is provided the use ofa compound of formula (I), or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for the treatment of diseases orconditions for which a bromodomain inhibitor is indicated.

STATEMENT OF USE

The compounds of formula (I) and salts thereof are bromodomaininhibitors, and thus are believed to have potential utility in thetreatment of diseases or conditions for which a bromodomain inhibitor isindicated.

Bromodomain inhibitors are believed to be useful in the treatment of avariety of diseases or conditions related to systemic or tissueinflammation, inflammatory responses to infection or hypoxia, cellularactivation and proliferation, lipid metabolism, fibrosis and in theprevention and treatment of viral infections.

Bromodomain inhibitors may be useful in the treatment of a wide varietyof acute or chronic autoimmune and/or inflammatory conditions such asrheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis,osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus,multiple sclerosis, inflammatory bowel disease (Crohn's disease andulcerative colitis), asthma, chronic obstructive airways disease,pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis(including atopic dermatitis), alopecia, vitiligo, bullous skindiseases, nephritis, vasculitis, hypercholesterolemia, atherosclerosis,Alzheimer's disease, Sjögren's syndrome, sialoadenitis, central retinalvein occlusion, branched retinal vein occlusion, Irvine-Gass syndrome(post cataract and post-surgical), retinitis pigmentosa, pars planitis,birdshot retinochoroidopathy, epiretinal membrane, cystic macular edema,parafoveal telengiectasis, tractional maculopathies, vitreomaculartraction syndromes, retinal detachment, neuroretinitis, idiopathicmacular edema, retinitis, dry eye (keratoconjunctivitis Sicca), vernalkeratoconjunctivitis, atopic keratoconjunctivitis, uveitis (such asanterior uveitis, pan uveitis, posterior uveitis, uveitis-associatedmacular edema), scleritis, diabetic retinopathy, diabetic macula edema,age-related macular dystrophy, hepatitis, pancreatitis, primary biliarycirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis,thyroiditis, Type I diabetes, Type II diabetes, giant cell arteritis,nephritis including lupus nephritis, vasculitis with organ involvementsuch as glomerulonephritis, vasculitis including giant cell arteritis,Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease,Kawasaki disease, Takayasu's Arteritis, pyoderma gangrenosum, vasculitiswith organ involvement and acute rejection of transplanted organs.

In one embodiment the acute or chronic autoimmune and/or inflammatorycondition is a disorder of lipid metabolism mediated via the regulationof APO-A1 such as hypercholesterolemia, atherosclerosis or Alzheimer'sdisease.

In another embodiment the acute or chronic autoimmune and/orinflammatory condition is a respiratory disorder such as asthma orchronic obstructive airways disease.

In another embodiment the acute or chronic autoimmune and/orinflammatory condition is a systemic inflammatory disorder such asrheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemiclupus erythematosus, multiple sclerosis or inflammatory bowel disease(Crohn's disease or Ulcerative colitis).

In another embodiment, the acute or chronic autoimmune and/orinflammatory condition is multiple sclerosis.

In another embodiment, the acute or chronic autoimmune and/orinflammatory condition is Type I diabetes.

In another embodiment, the acute or chronic autoimmune and/orinflammatory condition is rheumatoid arthritis.

Bromodomain inhibitors may be useful in the treatment of depression.

Bromodomain inhibitors may be useful in the treatment of diseases orconditions which involve inflammatory responses to infections withbacteria, viruses, fungi, parasites or their toxins, such as sepsis,acute sepsis, sepsis syndrome, septic shock, endotoxaemia, systemicinflammatory response syndrome (SIRS), multi-organ dysfunction syndrome,toxic shock syndrome, acute lung injury, ARDS (adult respiratorydistress syndrome), acute renal failure, fulminant hepatitis, burns,acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimerreactions, encephalitis, myelitis, meningitis, malaria and SIRSassociated with viral infections such as influenza, herpes zoster,herpes simplex and coronavirus. In one embodiment the disease orcondition which involves an inflammatory response to an infection withbacteria, a virus, fungi, a parasite or their toxins is acute sepsis.

Bromodomain inhibitors may be useful in the treatment of conditionsassociated with ischaemia-reperfusion injury such as myocardialinfarction, cerebro-vascular ischaemia (stroke), acute coronarysyndromes, renal reperfusion injury, organ transplantation, coronaryartery bypass grafting, cardio-pulmonary bypass procedures, pulmonary,renal, hepatic, gastro-intestinal or peripheral limb embolism.

Bromodomain inhibitors may be useful in the treatment of cardiovasculardiseases such as coronary artery diseases (for example, angina ormyocardial infarction), cerebro-vascular ischaemia (stroke),hypertensive heart disease, rheumatic heart disease, cardiomyopathy,atrial fibrillation, congenital heart disease, endocarditis, aorticaneurysms or peripheral artery disease.

Bromodomain inhibitors may be useful in the treatment of fibroticconditions such as idiopathic pulmonary fibrosis, renal fibrosis,post-operative stricture, keloid scar formation, scleroderma (includingmorphea) or cardiac fibrosis.

Bromodomain inhibitors may be useful in the treatment of viralinfections such as herpes simplex infections and reactivations, coldsores, herpes zoster infections and reactivations, chickenpox, shingles,human papilloma virus (HPV), human immunodeficiency virus (HIV),cervical neoplasia, adenovirus infections, including acute respiratorydisease, poxvirus infections such as cowpox or smallpox, or Africanswine fever virus. In one embodiment the viral infection is a HPVinfection of skin or cervical epithelia. In another embodiment the viralinfection is a latent HIV infection.

Bromodomain inhibitors may be useful in the treatment of a wide varietyof bone disorders such as osteoporosis, osteopenia, osteoarthritis andankylosing spondylitis.

Bromodomain inhibitors may be useful in the treatment of cancer,including hematological cancers (such as leukaemia, lymphoma andmultiple myeloma), epithelial cancers (including lung, breast or coloncarcinomas), midline carcinomas, or mesenchymal, hepatic, renal orneurological tumours.

Bromodomain inhibitors may be useful in the treatment of one or morecancers selected from brain cancer (gliomas), glioblastomas,Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease,breast cancer, inflammatory breast cancer, colorectal cancer, Wilm'stumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma,colon cancer, head and neck cancer, kidney cancer, lung cancer, livercancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreaticcancer, prostate cancer, sarcoma cancer, osteosarcoma, giant cell tumorof bone, thyroid cancer, lymphoblastic T-cell leukemia, chronicmyelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia,acute lymphoblastic leukemia, acute myelogenous leukemia, chronicneutrophilic leukemia, acute lymphoblastic T-cell leukemia,plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia,multiple myeloma, megakaryoblastic leukemia, acute megakaryocyticleukemia, promyelocytic leukemia, mixed lineage leukaemia,erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkinslymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicularlymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvalcancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor), NUT-midline carcinoma and testicularcancer.

In one embodiment the cancer is a leukaemia, for example a leukaemiaselected from acute monocytic leukemia, acute myelogenous leukemia,chronic myelogenous leukemia, chronic lymphocytic leukemia and mixedlineage leukaemia (MLL). In another embodiment the cancer is NUT-midlinecarcinoma. In another embodiment the cancer is multiple myeloma. Inanother embodiment the cancer is a lung cancer such as small cell lungcancer (SCLC). In another embodiment the cancer is a neuroblastoma. Inanother embodiment the cancer is Burkitt's lymphoma. In anotherembodiment the cancer is cervical cancer. In another embodiment thecancer is esophageal cancer. In another embodiment the cancer is ovariancancer. In another embodiment the cancer is breast cancer. In anotherembodiment the cancer is colarectal cancer.

Bromodomain inhibitors may be useful in the treatment of diseasesassociated with systemic inflammatory response syndrome, such as sepsis,burns, pancreatitis, major trauma, haemorrhage and ischaemia. In thisembodiment the bromodomain inhibitor would be administered at the pointof diagnosis to reduce the incidence of: SIRS, the onset of shock,multi-organ dysfunction syndrome, which includes the onset of acute lunginjury, ARDS, acute renal, hepatic, cardiac or gastro-intestinal injuryand mortality. In another embodiment the bromodomain inhibitor would beadministered prior to surgical or other procedures associated with ahigh risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS(multiple organ dysfunction syndrome). In a particular embodiment thedisease or condition for which a bromodomain inhibitor is indicated issepsis, sepsis syndrome, septic shock and endotoxaemia. In anotherembodiment, the bromodomain inhibitor is indicated for the treatment ofacute or chronic pancreatitis. In another embodiment the bromodomain isindicated for the treatment of burns.

The present invention thus provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in therapy. Thecompound of formula (I) or a pharmaceutically salt thereof can be usedin the treatment of diseases or conditions for which a bromodomaininhibitor is indicated.

The present invention thus provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment of adisease or condition for which a bromodomain inhibitor is indicated. Inone embodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofacute or chronic auto-immune and/or inflammatory conditions. In oneembodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofrheumatoid arthritis. In another embodiment there is provided a compoundof formula (I) or a pharmaceutically acceptable salt thereof for use inthe treatment of diseases or conditions which involve inflammatoryresponses to infections with bacteria, viruses, fungi, parasites ortheir toxins. In another embodiment there is provided a compound offormula (I) or a pharmaceutically acceptable salt thereof for use in thetreatment of conditions associated with ischaemia-reperfusion injury. Inanother embodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofcardiovascular diseases. In another embodiment there is provided acompound of formula (I) or a pharmaceutically acceptable salt thereoffor use in the treatment of fibrotic conditions. In another embodimentthere is provided a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use in the treatment of viral infections. Inanother embodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofbone disorders. In another embodiment there is provided a compound offormula (I) or a pharmaceutically acceptable salt thereof for use in thetreatment of cancer. In a further embodiment there is provided acompound of formula (I) or a pharmaceutically acceptable salt thereoffor use in the treatment of diseases associated with systemicinflammatory response syndrome.

Also provided is the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of diseases or conditions for which abromodomain inhibitor is indicated. In one embodiment there is providedthe use of a compound of formula (I) or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the treatment ofacute or chronic auto-immune and/or inflammatory conditions. In oneembodiment there is provided the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of rheumatoid arthritis. In anotherembodiment there is provided the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of diseases or conditions which involveinflammatory responses to infections with bacteria, viruses, fungi,parasites or their toxins. In another embodiment there is provided theuse of a compound of formula (I) or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for the treatment ofconditions associated with ischaemia-reperfusion injury. In anotherembodiment there is provided the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of cardiovascular diseases. In anotherembodiment there is provided the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of fibrotic conditions. In anotherembodiment there is provided the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of viral infections. In another embodimentthere is provided the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of cancer. In a further embodiment there isprovided the use of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for thetreatment of diseases associated with systemic inflammatory responsesyndrome.

Also provided is a method of treating diseases or conditions for which abromodomain inhibitor is indicated in a subject in need thereof whichcomprises administering a therapeutically effective amount of compoundof formula (I) or a pharmaceutically acceptable salt thereof. In oneembodiment there is provided a method of treating acute or chronicauto-immune and/or inflammatory conditions in a subject in need thereofwhich comprises administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.In one embodiment there is provided a method of treating rheumatoidarthritis in a subject in need thereof which comprises administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof. In another embodiment there isprovided a method of treating diseases or conditions which involveinflammatory responses to infections with bacteria, viruses, fungi,parasites or their toxins in a subject in need thereof which comprisesadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof. In anotherembodiment there is provided a method of treating conditions associatedwith ischaemia-reperfusion injury in a subject in need thereof whichcomprises administering a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof. In anotherembodiment there is provided a method of treating cardiovasculardiseases in a subject in need thereof which comprises administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof. In another embodiment there isprovided a method of treating fibrotic conditions in a subject in needthereof which comprises administering a therapeutically effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof. In another embodiment there is provided a method of treatingviral infections in a subject in need thereof which comprisesadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof. In anotherembodiment there is provided a method of treating cancer in a subject inneed thereof which comprises administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof. In a further embodiment there is provided a method oftreating diseases associated with systemic inflammatory responsesyndrome in a subject in need thereof which comprises administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

Suitably the subject in need thereof is a mammal, particularly a human.

The invention further provides for a method for inhibiting a bromodomainwhich comprises contacting the bromodomain with a compound of formula(I) or a pharmaceutically acceptable salt thereof.

As used herein the reference to the “treatment” of a particular diseaseor condition includes the prevention or prophylaxis of such a disease orcondition.

Pharmaceutical Compositions/Routes of Administration/Dosages

Compositions

While it is possible that for use in therapy, a compound of formula (I)as well as pharmaceutically acceptable salts thereof may be administeredas the raw chemical, it is common to present the active ingredient as apharmaceutical composition. The compounds of formula (I) andpharmaceutically acceptable salts thereof will normally, but notnecessarily, be formulated into pharmaceutical compositions prior toadministration to a patient. Accordingly, in another aspect there isprovided a pharmaceutical composition comprising a compound of formula(I), or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients. The compounds of formula (I) andpharmaceutically acceptable salts are as described above. Theexcipient(s) must be acceptable in the sense of being compatible withthe other ingredients of the composition and not deleterious to therecipient thereof. In accordance with another aspect of the inventionthere is also provided a process for the preparation of a pharmaceuticalcomposition including admixing a compound of formula (I), or apharmaceutically acceptable salt thereof, with one or morepharmaceutically acceptable excipients. The pharmaceutical compositioncan be used in the treatment of any of the conditions described herein.

In a further aspect the invention is directed to pharmaceuticalcompositions for the treatment or prophylaxis of a disease or conditionfor which a bromodomain inhibitor is indicated comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will be readily understood that they areeach preferably provided in substantially pure form, for example, atleast 85% pure, especially at least 98% pure (% in a weight for weightbasis).

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Preferred unit dosage compositions are those containing a daily dose orsub-dose, or an appropriate fraction thereof, of an active ingredient.Such unit doses may therefore be administered more than once a day.Preferred unit dosage compositions are those containing a daily dose orsub-dose (for administration more than once a day), as herein aboverecited, or an appropriate fraction thereof, of an active ingredient.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, inhaled, intranasal, topical (including buccal,sublingual or transdermal), ocular (including topical, intraocular,subconjunctival, episcleral, sub-Tenon), vaginal or parenteral(including subcutaneous, intramuscular, intravenous or intradermal)route. Such compositions may be prepared by any method known in the artof pharmacy, for example by bringing into association the activeingredient with the carrier(s) or excipient(s).

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein a safe and effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof can beextracted and then given to the patient such as with powders or syrups.Alternatively, the pharmaceutical compositions of the invention may beprepared and packaged in unit dosage form wherein each physicallydiscrete unit contains a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. When prepared in unit dosage form, thepharmaceutical compositions of the invention typically may contain, forexample, from 0.25 mg to 1 g, or from 0.5 mg to 500 mg, or from 1 mg to100 mg, of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

The pharmaceutical compositions of the invention typically contain onecompound of formula (I) or a pharmaceutically acceptable salt thereof.

The compound of formula (I) or a pharmaceutically acceptable saltthereof and the pharmaceutically acceptable excipient or excipients willtypically be formulated into a dosage form adapted for administration tothe patient by the desired route of administration. For example, dosageforms include those adapted for (1) oral administration such as tablets,capsules, caplets, pills, troches, powders, syrups, elixers,suspensions, solutions, emulsions, sachets, and cachets; (2) parenteraladministration such as sterile solutions, suspensions, and powders forreconstitution; (3) transdermal administration such as transdermalpatches; (4) rectal administration such as suppositories; (5) inhalationsuch as aerosols, solutions, and dry powders; and (6) topicaladministration such as creams, ointments, lotions, solutions, pastes,sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting of the compound or compoundsof formula (I) or pharmaceutically acceptable salts thereof onceadministered to the subject from one organ, or portion of the body, toanother organ, or portion of the body. Certain pharmaceuticallyacceptable excipients may be chosen for their ability to enhancesubjectcompliance.

Suitable pharmaceutically-acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweetners, flavouring agents, flavour-masking agents, colouring agents,anti-caking agents, humectants, chelating agents, plasticisers,viscosity increasing agents, antioxidants, preservatives, stabilisers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically-acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what other excipientsare present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically-acceptable excipients and may be useful inselecting suitable pharmaceutically-acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

Accordingly, in another aspect the invention is directed to process forthe preparation of a pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof and one ormore pharmaceutically-acceptable excipients which comprises mixing theingredients. A pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof may beprepared by, for example, admixture at ambient temperature andatmospheric pressure.

In one embodiment the pharmaceutical composition is adapted forparenteral administration, particularly intravenous administration.

In one embodiment the pharmaceutical composition is adapted for oraladministration.

In one embodiment the pharmaceutical composition is adapted for topicaladministration.

Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions (which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe composition isotonic with the blood of the intended recipient) andaqueous and non-aqueous sterile suspensions (which may includesuspending agents and thickening agents). The compositions may bepresented in unit-dose or multi-dose containers, for example sealedampoules and vials, and may be stored in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets.

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders suitable for incorporating intotablets or capsules may be prepared by reducing the compound to asuitable fine size (e.g. by micronisation) and mixing with a similarlyprepared pharmaceutical carrier such as an edible carbohydrate, forexample, starch or mannitol. Flavoring, preservative, dispersing andcoloring agent can also be present.

Capsules may be made by preparing a powder mixture, as described above,and filling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, glidants,lubricants, sweetening agents, flavours, disintegrating agents(disintegrants) and coloring agents can also be incorporated into themixture. Suitable binders include starch, gelatin, natural sugars suchas glucose or beta-lactose, corn sweeteners, natural and synthetic gumssuch as acacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegrantsinclude starch, methyl cellulose, agar, bentonite, xanthan gum and thelike. Tablets are formulated, for example, by preparing a powdermixture, granulating or slugging, adding a lubricant and disintegrantand pressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of formula (I) and pharmaceutically acceptable salts thereofcan also be combined with a free flowing inert carrier and compressedinto tablets directly without going through the granulating or sluggingsteps. A clear or opaque protective coating consisting of a sealing coatof shellac, a coating of sugar or polymeric material and a polishcoating of wax can be provided. Dyestuffs can be added to these coatingsto distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Compositions for oral administration may be designed to provide amodified release profile so as to sustain or otherwise control therelease of the therapeutically active agent.

Where appropriate, dosage unit compositions for oral administration canbe microencapsulated. The composition may be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

For compositions suitable and/or adapted for oral administration, thecompound of formula (I) or a pharmaceutically acceptable salt thereof,may be in a particle-size-reduced form e.g. obtained by micronisation.The preferable particle size of the size-reduced (e.g. micronised)compound or salt is defined by a D₅₀ value of about 0.5 to about 10microns (for example as measured using laser diffraction).

The compounds of formula (I) and pharmaceutically acceptable saltsthereof, can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, emulsions, lotions,powders, solutions, pastes, gels, foams, sprays, aerosols or oils. Suchpharmaceutical compositions may include conventional additives whichinclude, but are not limited to, preservatives, solvents to assist drugpenetration, co-solvents, emollients, propellants, viscosity modifyingagents (gelling agents), surfactants and carriers. In one embodimentthere is provided a pharmaceutical composition adapted for topicaladministration which comprises between 0.01-10%, or between 0.01-1% ofthe compound of formula (I), or a pharmaceutically acceptable saltthereof, by weight of the composition.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions are preferably applied as a topical ointment,cream, gel, spray or foam. When formulated in an ointment, the activeingredient may be employed with either a paraffinic or a water-miscibleointment base. Alternatively, the active ingredient may be formulated ina cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.Compositions to be administered to the eye will have ophthalmicallycompatible pH and osmolality. One or more ophthalmically acceptable pHadjusting agents and/or buffering agents can be included in acomposition of the invention, including acids such as acetic, boric,citric, lactic, phosphoric and hydrochloric acids; bases such as sodiumhydroxide, sodium phosphate, sodium borate, sodium citrate, sodiumacetate, and sodium lactate; and buffers such as citrate/dextrose,sodium bicarbonate and ammonium chloride. Such acids, bases, and bufferscan be included in an amount required to maintain pH of the compositionin an ophthalmically acceptable range. One or more ophthalmicallyacceptable salts can be included in the composition in an amountsufficient to bring osmolality of the composition into an ophthalmicallyacceptable range. Such salts include those having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions.

The ocular delivery device may be designed for the controlled release ofone or more therapeutic agents with multiple defined release rates andsustained dose kinetics and permeability. Controlled release may beobtained through the design of polymeric matrices incorporatingdifferent choices and properties of biodegradable/bioerodable polymers(e.g. poly(ethylene vinyl) acetate (EVA), superhydrolyzed PVA),hydroxyalkyl cellulose (HPC), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), polycaprolactone, poly(glycolic) acid, poly(lactic)acid, polyanhydride, of polymer molecular weights, polymercrystallinity, copolymer ratios, processing conditions, surface finish,geometry, excipient addition and polymeric coatings that will enhancedrug diffusion, erosion, dissolution and osmosis.

Pharmaceutical compositions for ocular delivery also include in situgellable aqueous composition. Such a composition comprises a gellingagent in a concentration effective to promote gelling upon contact withthe eye or with lacrimal fluid. Suitable gelling agents include but arenot limited to thermosetting polymers. The term “in situ gellable” asused herein is includes not only liquids of low viscosity that form gelsupon contact with the eye or with lacrimal fluid, but also includes moreviscous liquids such as semi-fluid and thixotropic gels that exhibitsubstantially increased viscosity or gel stiffness upon administrationto the eye. See, for example, Ludwig (2005) Adv. Drug Deliv. Rev. 3;57:1595-639, herein incorporated by reference for purposes of itsteachings of examples of polymers for use in ocular drug delivery.

Dosage forms for nasal or inhaled administration may conveniently beformulated as aerosols, solutions, suspensions, gels or dry powders.

For compositions suitable and/or adapted for inhaled administration, itis preferred that the compound of formula (I) or a pharmaceuticallyacceptable salt thereof, is in a particle-size-reduced form e.g.obtained by micronisation. The preferable particle size of thesize-reduced (e.g. micronised) compound or salt is defined by a D₅₀value of about 0.5 to about 10 microns (for example as measured usinglaser diffraction).

Aerosol formulations, e.g. for inhaled administration, can comprise asolution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent. Aerosolformulations can be presented in single or multidose quantities insterile form in a sealed container, which can take the form of acartridge or refill for use with an atomising device or inhaler.Alternatively the sealed container may be a unitary dispensing devicesuch as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve (metered dose inhaler) which is intended for disposalonce the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferablycontains a suitable propellant under pressure such as compressed air,carbon dioxide or an organic propellant such as a hydrofluorocarbon(HFC). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropaneand 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also takethe form of a pump-atomiser. The pressurised aerosol may contain asolution or a suspension of the active compound. This may require theincorporation of additional excipients e.g. co-solvents and/orsurfactants to improve the dispersion characteristics and homogeneity ofsuspension formulations. Solution formulations may also require theaddition of co-solvents such as ethanol.

For pharmaceutical compositions suitable and/or adapted for inhaledadministration, the pharmaceutical composition may be a dry powderinhalable composition. Such a composition can comprise a powder basesuch as lactose, glucose, trehalose, mannitol or starch, the compound offormula (I) or a pharmaceutically acceptable salt thereof (preferably inparticle-size-reduced form, e.g. in micronised form), and optionally aperformance modifier such as L-leucine or another amino acid and/ormetal salt of stearic acid such as magnesium or calcium stearate.Preferably, the dry powder inhalable composition comprises a dry powderblend of lactose e.g. lactose monohydrate and the compound of formula(I) or salt thereof. Such compositions can be administered to thepatient using a suitable device such as the DISKUS® device, marketed byGlaxoSmithKline which is for example described in GB 2242134 A.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be formulated as a fluid formulation for delivery from afluid dispenser, for example a fluid dispenser having a dispensingnozzle or dispensing orifice through which a metered dose of the fluidformulation is dispensed upon the application of a user-applied force toa pump mechanism of the fluid dispenser. Such fluid dispensers aregenerally provided with a reservoir of multiple metered doses of thefluid formulation, the doses being dispensable upon sequential pumpactuations. The dispensing nozzle or orifice may be configured forinsertion into the nostrils of the user for spray dispensing of thefluid formulation into the nasal cavity. A fluid dispenser of theaforementioned type is described and illustrated in WO-A-2005/044354.

A therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, will depend upon a number offactors including, for example, the age and weight of the patient, theprecise condition requiring treatment and its severity, the nature ofthe formulation, and the route of administration, and will ultimately beat the discretion of the attendant physician or veterinarian. In thepharmaceutical composition, each dosage unit for oral or parenteraladministration preferably contains from 0.01 mg to 3000 mg, morepreferably 0.5 mg to 1000 mg, of a compound of formula (I) or apharmaceutically acceptable salt thereof, calculated as the free base.Each dosage unit for nasal or inhaled administration preferably containsfrom 0.001 mg to 50 mg, more preferably 0.01 mg to 5 mg, of a compoundof the formula (I) or a pharmaceutically acceptable salt thereof,calculated as the free base.

The pharmaceutically acceptable compounds of formula (I) andpharmaceutically acceptable salts thereof, can be administered in adaily dose (for an adult patient) of, for example, an oral or parenteraldose of 0.01 mg to 3000 mg per day, 0.5 mg to 1000 mg per day or 100 mgto 2500 mg per day, or a nasal or inhaled dose of 0.001 mg to 50 mg perday or 0.01 mg to 5 mg per day, of the compound of the formula (I) or apharmaceutically acceptable salt thereof, calculated as the free base.This amount may be given in a single dose per day or more usually in anumber (such as two, three, four, five or six) of sub-doses per day suchthat the total daily dose is the same. An effective amount of a saltthereof, may be determined as a proportion of the effective amount ofthe compound of formula (I) per se.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be employed alone or in combination with other therapeuticagents. Combination therapies according to the present invention thuscomprise the administration of at least one compound of formula (I) or apharmaceutically acceptable salt thereof, and the use of at least oneother therapeutically active agent. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one compound of formula (I) or a pharmaceutically acceptable saltthereof, and at least one other therapeutically active agent. Thecompound(s) of formula (I) and pharmaceutically acceptable saltsthereof, and the other therapeutically active agent(s) may beadministered together in a single pharmaceutical composition orseparately and, when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) and pharmaceutically acceptable saltsthereof, and the other therapeutically active agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect. Thus in a further aspect, there isprovided a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof, together with one or moreother therapeutically active agents.

Thus in one aspect, the compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and pharmaceutical compositions comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof,according to the invention may be used in combination with or includeone or more other therapeutic agents, for example selected fromantibiotics, anti-virals, glucocorticosteroids, muscarinic antagonists,beta-2 agonists and Vitamin D3 analogues. In a further embodiment acompound of formula (I) or a pharmaceutically acceptable salt thereofmay be used in combination with a further therapeutic agent which issuitable for the treatment of cancer. Examples of such furthertherapeutic agents are desfibed in Cancer Principles and Practice ofOncology by V. T. Devita and S. Hellman (editors), 6^(th) edition(2001), Lippincott Williams & Wilkins Publishers. A person of ordinaryskill in the art would be able to discern which combinations of agentswould be useful based on the particular characteristics of the drugs andthe cancer involved. Further therapeutic agents to be used incombination with the compound of formula (I) or a pharmaceuticallyacceptable salt thereof include, but are not limited to,anti-microtubule agents (such as diterpenoids and vinca alkaloids);platinum coordination complexes; alkylating agents (such as nitrogenmustards, oxazaphosphorines, alkylsulphonates, nitrosoureas, andtriazenes); antibiotic agents (such as anthracyclins, actinomycins andbleomycins); topoisomerase II inhibitors (such as epipodophyllotoxins);antimetabolites (such as purine and pyrimidine analogues and anti-folatecompounds); topoisomerase I inhibitors (such as camptothecins; hormonesand hormonal analogues); signal transduction pathway inhibitors (such astyropsine receptor inhibitors); non-receptor tyrosine kinaseangiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents;epigenetic or transcriptional modulators (such as histone deacetylaseinhibitors) and cell cycle signaling inhibitors.

It will be appreciated that when the compound of formula (I) or apharmaceutically acceptable salt thereof, is administered in combinationwith other therapeutic agents normally administered by the inhaled,intravenous, oral or intranasal route, that the resultant pharmaceuticalcomposition may be administered by the same routes. Alternatively theindividual components of the composition may be administered bydifferent routes.

One embodiment of the invention encompasses combinations comprising oneor two other therapeutic agents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,for example as alkali metal or amine salts or as acid addition salts, orprodrugs, or as esters, for example lower alkyl esters, or as solvates,for example hydrates, to optimise the activity and/or stability and/orphysical characteristics, such as solubility, of the therapeuticingredient. It will be clear also that, where appropriate, thetherapeutic ingredients may be used in optically pure form.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus pharmaceuticalcompositions comprising a combination as defined above together with apharmaceutically acceptable diluent or carrier represent a furtheraspect of the invention.

General Synthetic Routes

The compounds of the invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out in thefollowing schemes, and can be readily adapted to prepare other compoundsof the invention. Specific compounds of the invention are prepared inthe Examples section.

Compounds of formula (I) may be prepared as described in any of theSchemes below:

wherein R¹, R², R³ and R⁴ are as described above, Hal is chlorine orbromine and X is a C₁₋₆alkyl group.

In respect of the steps shown in Scheme 1 above the following reactionconditions may be utilised:

Step 1: is an alkylation and may be carried out using an alkyl or benzylhalide of formula R⁴CH(R³)Hal, such as an alkylbromide of formulaR⁴CH(R³)Br, in the presence of an inorganic base, such as sodiumhydride, in a suitable solvent, preferably an aprotic solvent, such asDMF, THF or 2-MeTHF, at a suitable temperature, such as 0° C.Step 2: is base hydrolysis and may be carried out using any suitableinorganic base, such as LiOH, in a suitable solvent or solvent mixture,such as a mixture of methanol and THF, at a suitable temperature, suchas room temperature.Step 3: is an amide coupling reaction consisting of two steps. Step 3a,to produce the acid chloride, may be carried out using a chlorinatingagent, such as oxalyl chloride, in the presence of a suitable catalyst,such as DMF, in a suitable solvent, such as DCM, at a suitabletemperature, such as room temperature. Step 3b may be carried out usingan amine reagent, R¹—NH₂, optionally in the presence of a tertiaryamine, such as triethylamine, in a suitable solvent, such as THF, at asuitable temperature, such as 0° C.Step 4: is an amine displacement reaction and may be carried out usingan amine reagent, R¹—NH₂, in a suitable solvent or solvent mixture, suchas a mixture of water and methanol, at a suitable temperature, such as50° C.Step 5: is a carbonylation reaction and may be carried out using analcohol reagent, XOH (X is a C₁₋₆alkyl group), in the presence of atertiary amine, such as triethylamine, in the presence of a palladiumcatalyst, such as palladium acetate, in the presence of a phosphineligand, such as dppb, in the presence of carbon monoxide, in a suitablesolvent, such as DMSO, at a suitable temperature, such as 100° C.Step 6: is a hydrolysis step and may be carried out using an inorganicbase, such as NaOH or LiOH, in a suitable solvent or solvent mixture,such as methanol and THF, at a suitable temperature, such as roomtemperature.Step 7: is an amide coupling reaction and may be carried out using anamine reagent, R²—NH₂, in the presence of a suitable tertiary amine,such as triethylamine or DIPEA, in the presence of a suitable amidecoupling reactant, such as HATU, in a suitable solvent, such as DCM orDMF, at a suitable temperature, such as room temperature.Step 8: is a carbonylation reaction and may be carried out using a metalcarbonyl complex, such as dicobalt octacarbonyl, in the presence of aphosphine ligand, such as Xantphos, in the presence of a suitablepalladium catalyst, such as palladium (II) acetate, in the presence of anucleophilic catalyst, such as DMAP, in the presence of a suitablesolvent, such as THF, at a suitable temperature, such as 80° C.Step 9: is a displacement reaction and may be carried out using an aminereagent, R²—NH₂, in the presence of a nucleophilic catalyst, such asDMAP, in the presence of a tertiary amine, such as triethylamine, in thepresence of a suitable solvent, such as THF, at a suitable temperature,such as 45° C.Step 10: is an optional deprotection step to remove a protecting group,such as BOC and may be carried out using an acid such as TFA, in thepresence of a suitable solvent, such as DCM, at a suitable temperature,such as room temperature.Step 11: is a pyridone formation and may be carried out using an alkylor benzyl amine, such as R⁴CH(R³)NH₂, in a suitable solvent or solventmixture, such as DMF and THF, with the addition of a suitable amidecoupling reagent, such as EDC, a suitable nucleophilic catalyst, such asDMAP, and a suitable temperature, such as room temperature.Step 12: is a bromination reaction and may be carried out using asuitable brominating reactant, such as NBS, in a suitable solvent, suchas 2-MeTHF, at a suitable temperature, such as room temperature.

wherein R¹, R², R³ and R⁴ are as described above, Y is a C₁₋₆alkyl groupand Hal is bromine or chlorine.

In respect of the steps shown in Scheme 2 above the following reactionconditions may be utilised:

Step 1: is an acid chloride formation, and may be carried out using achlorinating agent, such as oxalyl chloride, in the presence of asuitable catalyst, such as DMF, in a suitable solvent, such as DCM, at asuitable temperature, such as room temperature.

Step 2: is an amine displacement reaction, and may be carried out usingan amine reagent, R¹—NH₂, in the presence of a tertiary amine, such astriethylamine, in a suitable solvent, such as THF, at a suitabletemperature, such as 0° C.

Step 3: is a carbonylation reaction and may be carried out using analcohol reagent, YOH (Y is a C₁₋₆alkyl group), in the presence of atertiary amine, such as triethylamine, in the presence of a palladiumcatalyst, such as palladium (II) acetate, in the presence of a phosphineligand, such as dppb, in the presence of carbon monoxide, in a suitablesolvent, such as DMSO, at a suitable temperature, such as 100° C.Step 4: is a demethylation reaction and may be carried out using ademethylating agent, such as NaI with TMS-Cl, in a suitable solvent,such as acetonitrile, at a suitable temperature, such as roomtemperature.Step 5: is an alkylation and may be carried out using an alkyl or benzylhalide such as a R⁴CH(R³)Br or R⁴CH(R³)Cl, in the presence of aninorganic base, such as potassium carbonate, in a suitable solvent, suchas DMF, at a suitable temperature, such as 90° C.Step 6: is a Mitsunobu reaction and may be carried out using an alcohol,such as R⁴CH(R³)OH, a Mitsunobu reagent, such as DIAD in the presence ofa phosphine, such as triphenyl phosphine, or2-(tributylphosphoranylidene)acetonitrile, in a suitable solvent, suchas toluene, at a suitable temperature, such as room temperature or 120°C.Step 7: is a hydrolysis step and may be carried out using an inorganicbase, such as NaOH or LiOH, in a suitable solvent or solvent mixture,such as methanol and THF or 1,4-dioxane and water, at a suitabletemperature, such as room temperature.Step 8: is an amide coupling reaction and may be carried out using anamine reagent, R²—NH₂, in the presence of a suitable tertiary amine,such as triethylamine or DIPEA, in the presence of an amide couplingreactant, such as HATU, in a suitable solvent, such as DCM or DMF, at asuitable temperature, such as room temperature.Step 9: is an optional deprotection step to remove a protecting group,such as BOC and may be carried out using an acid such as TFA, in thepresence of a suitable solvent, such as DCM, at a suitable temperature,such as room temperature.Step 10: is an optional chiral separation, using a suitable chiral HPLCcolumn and a suitable solvent system.Step 11: is a hydrolysis step and may be carried out using an inorganicbase, such as NaOH or LiOH, in a suitable solvent or solvent mixture,such as methanol and THF or 1,4-dioxane and water, at a suitabletemperature, such as room temperature.Step 12: is an amide coupling reaction and may be carried out using anamine reagent, R²—NH₂, in the presence of a suitable tertiary amine,such as triethylamine or DIPEA, in the presence of an amide couplingreactant, such as HATU, in a suitable solvent, such as DCM or DMF, at asuitable temperature, such as room temperature.Step 13: is a demethylation reaction and may be carried out using ademethylating agent, such as NaI with TMS-Cl, in a suitable solvent,such as acetonitrile, at a suitable temperature, such as roomtemperature.Step 14: is an alkylation and may be carried out using an alkyl orbenzyl halide such as a R⁴CH(R³)Br or R⁴CH(R³)Cl, in the presence of aninorganic base, such as potassium carbonate, in a suitable solvent, suchas DMF, at a suitable temperature, such as 90° C.

wherein R¹, R², R³ and R⁴ are as described above and Hal is bromine orchlorine.

In respect of the steps shown in Scheme 3 above the following reactionconditions may be utilised:

Step 1: is an benzylation and may be carried out using a suitable silversalt, such as silver carbonate, a benzyl halide such as benzyl bromide,a suitable solvent, such as chloroform and heated for example, underreflux.

Step 2: is a hydrolysis step and may be carried out using an inorganicbase, such as NaOH or LiOH, in a suitable solvent or solvent mixture,such as methanol and THF or 1,4-dioxane and water, at a suitabletemperature, such as room temperature.

Step 3: is an amide coupling reaction consisting of two steps. Step 3a,to produce the acid chloride, may be carried out using a chlorinatingagent, such as oxalyl chloride, in the presence of a suitable catalyst,such as DMF, in a suitable solvent, such as DCM, at a suitabletemperature, such as room temperature. Step 3b may be carried out usingan amine reagent, R¹—NH₂, in a suitable solvent, such as THF, at asuitable temperature, such as 0° C.Step 4: is a carbonylation reaction and may be carried out using2,4,6-trichlorophenyl formate, in the presence of a phosphine ligand,such as Xantphos, in the presence of a suitable palladium catalyst, suchas palladium (II) acetate, in the presence of a tertiary amine, such astriethylamine, in the presence of a suitable solvent, such as toluene,at a suitable temperature, such as 80° C.Step 5: is a displacement reaction and may be carried out using an aminereagent, R²—NH₂, in the presence of a nucleophilic catalyst, such asDMAP, in the presence of a tertiary amine, such as triethylamine, in thepresence of a suitable solvent, such as THF, at a suitable temperature,such as 45° C.Step 6: is a debenzylation and may be carried out using a suitable acid,such as TFA, at a suitable temperature, such as 80° C.Step 7: is a Mitsunobu reaction and may be carried out using an alcohol,such as R⁴CH(R³)OH, a Mitsunobu reagent, such as DIAD in the presence ofa phosphine, such as triphenyl phosphine, or2-(tributylphosphoranylidene)acetonitrile, in a suitable solvent, suchas toluene, at a suitable temperature, such as room temperature or 120°C.Step 8: is an alkylation and may be carried out using an alkyl or benzylhalide such as a R⁴CH(R³)Br or R⁴CH(R³)Cl, in the presence of aninorganic base, such as potassium carbonate, in a suitable solvent, suchas DMF, at a suitable temperature, such as 90° C.Step 9: is an optional deprotection step to remove a protecting group,such as BOC and may be carried out using an acid such as TFA, in thepresence of a suitable solvent, such as DCM, at a suitable temperature,such as room temperature.Step 10: is an optional deprotection step to cleave a sulfonamide group,such as tosyl and may be carried out using an inorganic base, such ascesium carbonate, in the presence of a suitable solvent or solventmixture, such as methanol and THF, at a suitable temperature, such as70° C.

wherein R¹, R², R³ and R⁴ are as described above and Hal is chorine orbromine.

In respect of the steps shown in Scheme 4 above the following reactionconditions may be utilised:

Step 1: is an amine displacement reaction and may be carried out usingan amine reagent, R¹—NH₂, in a suitable solvent, such as THF, at asuitable temperature, such as under reflux.

Step 2: is an alkylation and may be carried out using an alkyl or benzylhalide such as a R⁴CH(R³)Br or R⁴CH(R³)Cl, in the presence of aninorganic base, such as potassium carbonate, in a suitable solvent, suchas methanol or DMF, at a suitable temperature, such as 65° C. or 90° C.Step 3: is an amino carbonylation reaction and may be carried out usingan amine reagent such as R²—NH₂, a metal carbonyl complex, such asdicobalt octacarbonyl, in the presence of a phosphine ligand, such asXantphos or Catacxium A, in the presence of a suitable palladiumcatalyst, such as palladium (II) acetate, in the presence of a suitablenucleophilic catalyst, such as DMAP, in the presence of a suitablesolvent, such as 1,4 dioxane or THF, at a suitable temperature, such as80° C.Step 4: is an optional deprotection step to cleave a sulfonamide group,such as tosyl and may be carried out using an inorganic base such ascesium carbonate, in the presence of a suitable solvent or solventmixture, such as methanol and THF, at a suitable temperature, such as70° C.Step 5: is an optional deprotection step to remove a protecting group,such as BOC and may be carried out using a suitable acid, such as TFA,in the presence of a suitable solvent, such as DCM, at a suitabletemperature, such as room temperature.

Compounds of Formulae (VIII), (XIII), (XX), (XXIII) and (XXIX) arecommercially available from, for example, Sigma Aldrich, Fluorochem,Apollo Scientific or CombiBlocks. Compounds of formulae R¹—NH₂, XOH,R²—NH₂R⁴CH(R³)OH, R³CH(R³)NH₂ and R⁴CH(R³)Hal are either commerciallyavailable from the suppliers mentioned above or can by made by methodswell known in the art or described herein.

Accordingly, in one embodiment there is provided a process for thepreparation of a compound of formula (I) by the reaction of a compoundof formula (II) with an amine of formula (XXVI)

wherein R¹, R², R³ and R⁴ are as hereinbefore defined; in the presenceof a nucleophilic catalyst, such as DMAP, in the presence of a tertiaryamine, such as triethylamine, in the presence of a suitable solvent,such as THF, at a suitable temperature, such as 45° C. This step may befollowed by removal of any protecting group, if required, followed bypreparation of a salt, if required.

In a second embodiment there is provided a process for the preparationof a compound of formula (I) by the reaction of a compound of formula(III) with an amine of formula (XXVI)

wherein R¹, R², R³ and R⁴ are as hereinbefore defined; in the presenceof a metal carbonyl complex, such as dicobalt octacarbonyl, in thepresence of a phosphine ligand, such as Xantphos or Catacxium A, in thepresence of a suitable nucleophilic catalyst, such as DMAP, in thepresence of a suitable solvent, such as 1,4 dioxane or THF, at asuitable temperature, such as 80° C. This step may be followed byremoval of any protecting group, if required, followed by preparation ofa salt, if required.

In a third embodiment there is provided a process for the preparation ofa compound of formula (I) by the reaction of a compound of formula (IV)with an amine of formula (XXVI)

wherein R¹, R², R³ and R⁴ are as hereinbefore defined; in the presenceof an amide coupling reagent, such as HATU, a tertiary amine, such astriethylamine or DIPEA, in the presence of a suitable solvent, such asDCM or DMF, at a suitable temperature, such as room temperature. Thisstep may be followed by removal of any protecting group, if required,followed by preparation of a salt, if required.

In a fourth embodiment there is provided a process for the preparationof a compound of formula (I) by the reaction of a compound of formula(XIV) with a compound of formula (XXVII)

wherein R¹, R², R³ and R⁴ are as hereinbefore defined and Hal ischlorine or bromine; in the presence of an inorganic base, such aspotassium carbonate, in a suitable solvent, such as DMF, at a suitabletemperature, such as 90° C. This step may be followed by removal of anyprotecting group, if required, followed by preparation of a salt, ifrequired.

In a fifth embodiment there is provided a process for the preparation ofa compound of formula (I) by the reaction of a compound of formula (XIV)with a compound of formula (XXVIII)

R¹, R², R³ and R⁴ are as hereinbefore defined; in the presence of aMitsunobu reagent, such as 2-(tributylphosphoranylidene)acetonitrile orDIAD in the presence of a phosphine, such as triphenyl phosphine, in asuitable solvent, such as toluene, at a suitable temperature, such as120° C. or room temperature. This step may be followed by removal of anyprotecting group, if required, followed by preparation of a salt, ifrequired.

It will be appreciated by those skilled in the art that it may beadvantageous to protect one or more functional groups of the compoundsdescribed above. Examples of protecting groups and the means for theirremoval can be found in T. W. Greene ‘Protective Groups in OrganicSynthesis’ (4th edition, J. Wiley and Sons, 2006), incorporated hereinby reference as it relates to such procedures.

Suitable amine protecting groups include acyl (e.g. acetyl, carbamate(e.g. 2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl ort-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed byacid mediated cleavage (e.g. using an acid such as hydrochloric acid indioxane or trifluoroacetic acid in dichloromethane) or reductively (e.g.hydrogenolysis of a benzyl or benzyloxycarbonyl group or reductiveremoval of a 2′,2′,2′-trichloroethoxycarbonyl group using zinc in aceticacid) as appropriate. Other suitable amine protecting groups includetrifluoroacetyl (—C(O)CF₃) which may be removed by base catalysedhydrolysis.

It will be appreciated that in any of the routes described above, theprecise order of the synthetic steps by which the various groups andmoieties are introduced into the molecule may be varied. It will bewithin the skill of the practitioner in the art to ensure that groups ormoieties introduced at one stage of the process will not be affected bysubsequent transformations and reactions, and to select the order ofsynthetic steps accordingly.

Certain intermediate compounds described above form a yet further aspectof the invention.

For any of the hereinbefore described reactions or processes,conventional methods of heating and cooling may be employed, for exampletemperature-regulated oil-baths or temperature-regulated hot-blocks, andice/salt baths or dry ice/acetone baths respectively. Conventionalmethods of isolation, for example extraction from or into aqueous ornon-aqueous solvents may be used. Conventional methods of drying organicsolvents, solutions, or extracts, such as shaking with anhydrousmagnesium sulfate, or anhydrous sodium sulfate, or passing through ahydrophobic frit, may be employed. Conventional methods of purification,for example crystallisation and chromatography, for example silicachromatography or reverse-phase chromatography, may be used as required.Crystallisation may be performed using conventional solvents such asethyl acetate, methanol, ethanol, or butanol, or aqueous mixturesthereof. It will be appreciated that specific reaction times andtemperatures may typically be determined by reaction-monitoringtechniques, for example thin-layer chromatography and LC-MS.

EXAMPLES

General Methods

General Experimental Details

All temperatures referred to are in ° C.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety. Unless otherwise noted, all starting materials were obtainedfrom commercial suppliers and used without further purification.Specifically, the following abbreviations may be used in the examplesand throughout the specification:

Abbreviations

-   AcOH acetic acid-   BBr₃ boron tribromide-   BOC/Boc tert-butyloxycarbonyl-   BuLi butyllithium-   Cs₂CO₃ cesium carbonate-   CHCl₃ chloroform-   Cobalt carbonyl dicobalt octacarbonyl-   CV column volume-   DMSO-d₆ deuterated dimethylsulfoxide-   DCM dichloromethane-   DIAD diisopropyl azodicarboxylate-   DIBAL-H diisobutylaluminium hydride-   DIPEA diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   DPPA diphenylphosphoryl azide-   dppb 1,4-bis(diphenylphosphino)butane-   EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et₃N triethylamine-   EtOAc ethyl acetate-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HCl hydrochloric acid-   HCO₂H formic acid-   IPA isopropyl alcohol-   Isolera Biotage Flash purification system-   K₂CO₃ potassium carbonate-   KOH potassium hydroxide-   LCMS liquid chromatography-mass spectrometry-   LiOH lithium hydroxide-   M molar (concentration)-   MDAP mass directed autoprep-   MeCN acetonitrile-   MeI methyl iodide-   MeOH methanol-   2-MeTHF 2-methyl tetrahydrofuran-   MgSO₄ magnesium sulphate-   min minute(s)-   MTBE methyl tert-butyl ether-   N normal (concentration)-   N₂ nitrogen-   Na₂CO₃ sodium carbonate-   NaI sodium iodide-   NaH sodium hydride-   NaOH sodium hydroxide-   Na(OAc)₃BH sodium triacetoxy borohydride-   Na₂SO₄ sodium sulphate-   NBS N-bromosuccinimide-   NEt₃ triethylamine-   NMP N-methyl-2-pyrrolidone-   NUT nuclear protein in testis-   Pd/C palladium on carbon-   PPh₃ triphenylphosphine-   RBF round bottomed flask-   Rt retention time-   rt room temperature-   sat saturated-   SCX Isolute strong cation exchange sorbent SPE-   SiO₂ silicon dioxide-   SNAP Biotage (silica) flash chromatography cartridge-   SP4 Biotage Flash purification system-   SPE solid phase extraction-   TBME tert-butyl methyl ether-   Tf₂O trifluoromethanesulfonic anhydride-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCl/TMS-Cl trimethylsilyl chloride-   TLC Thin layer chromatography-   Ts tosyl-   UPLC ultra performance liquid chromatograpy-   XantPhos    1,1′-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis[1,1-diphenylphosphine

The names of the following compounds have been obtained using thecompound naming programme “ACD Name Pro 6.02” or using the namingfunctionality of ChemDraw Ultra 12.0.

LCMS Methodology

Formic Method

LC Conditions

The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (50mm×2.1 mm, i.d. 1.7 μm packing diameter) at 40° C.

The solvents employed were:

A=0.1% v/v solution of formic acid in water

B=0.1% v/v solution of formic acid in acetonitrile

The gradient employed was:

Flow rate Time (min) (mL/min) % A % B 0 1 97 3 1.5 1 5 95 1.9 1 5 95 2.01 97 3

The UV detection was a summed signal from wavelength of 210 nm to 350nm.

MS Conditions

MS: Waters ZQ

Ionisation mode: Alternate-scan positive and negative electrospray

Scan range: 100 to 1000 AMU

Scan time: 0.27 sec

Inter scan delay: 0.10 sec

High pH Method

LC Conditions

The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (50mm×2.1 mm, i.d. 1.7 μm packing diameter) at 40° C.

The solvents employed were:

A=10 mM ammonium hydrogen carbonate in water adjusted to pH10 withammonia solution

B=acetonitrile

The gradient employed was:

Flow rate Time (min) (mL/min) % A % B 0 1 97 3 0.05 1 97 3 1.5 1 5 951.9 1 5 95 2.0 1 97 3

The UV detection was a summed signal from wavelength of 210 nm to 350nm.

MS Conditions

MS: Waters ZQ

Ionisation mode: Alternate-scan positive and negative electrospray

Scan range: 100 to 1000 AMU

Scan time: 0.27 sec

Inter scan delay: 0.10 sec

TFA Method

LC Conditions

The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (50mm×2.1 mm, i.d. 1.7 μm packing diameter) at 40° C.

The solvents employed were:

A=0.1% v/v solution of trifluoroacetic acid in water

B=0.1% v/v solution of trifluoroacetic acid in acetonitrile

The gradient employed was:

Flow rate Time (min) (mL/min) % A % B 0 1 95 5 1.5 1 5 95 1.9 1 5 95 2.01 95 5

The UV detection was a summed signal from wavelength of 210 nm to 350nm.

MS Conditions

MS Waters ZQ

Ionisation mode Alternate-scan positive and negative electrospray

Scan range 100 to 1000 AMU

Scan time 0.27 sec

Inter scan delay: 0.10 sec

General MDAP Purification Methods

Listed below are examples of mass-directed autopreparativechromatography (MDAP) methods that have been used or may be used incompound purification.

MDAP (High pH).

The HPLC analysis was conducted on an Xselect CSH C18 column (150 mm×30mm i.d. 5 μm packing diameter) at ambient temperature, eluting with 10mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution(Solvent A) and acetonitrile (Solvent B) using an elution gradient ofbetween 0 and 100% Solvent B over 15 or 25 minutes.

The UV detection was an averaged signal from wavelength of 210 nm to 350nm. The mass spectra were recorded on a Waters ZQ Mass Spectrometerusing alternate-scan positive and negative electrospray. Ionisation datawas rounded to the nearest integer.

MDAP (Formic).

The HPLC analysis was conducted on an Xselect CSH C18 column (150 mm×30mm i.d. 5 μm packing diameter) at ambient temperature, eluting with 0.1%formic acid in water (Solvent A) and 0.1% formic acid in acetonitrile(Solvent B) using an elution gradient of between 0 and 100% solvent Bover 15 or 25 minutes.

The UV detection was an averaged signal from wavelength of 210 nm to 350nm. The mass spectra were recorded on a Waters ZQ Mass Spectrometerusing alternate-scan positive and negative electrospray. Ionisation datawas rounded to the nearest integer.

MDAP (TFA).

The HPLC analysis was conducted on an Xselect CSH C18 column (150 mm×30mm i.d. 5 μm packing diameter) at ambient temperature, eluting with 0.1%v/v solution of trifluoroacetic acid in water (Solvent A) and 0.1% v/vsolution of trifluoroacetic acid in acetonitrile (Solvent B) using anelution gradient of between 0 and 100% solvent B over 15 or 25 minutes.

The UV detection was an averaged signal from wavelength of 210 nm to 350nm. The mass spectra were recorded on a Waters ZQ Mass Spectrometerusing alternate-scan positive and negative electrospray. Ionisation datawas rounded to the nearest integer.

NMR

Spectra were run on either a 400 MHz or 600 MHz NMR machine at either302 K or at 392-393 K for VT spectra.

Intermediate 1: tert-Butyl4-(hydroxymethyl)-1H-benzo[d]imidazole-1-carboxylate

To a solution of (1H-benzo[d]imidazol-7-yl)methanol (200 mg, 1.350 mmol,commercially available from, for example, Apollo Scientific) inacetonitrile (10.799 mL) and water (2.70 mL) was added sodiumbicarbonate (227 mg, 2.70 mmol) and Boc₂O (0.431 mL, 1.856 mmol). Themixture was stirred for 4 h at rt. The reaction mixture was diluted withethyl acetate (70 mL) and washed with 10% aqueous citric acid (3×25 mL).LCMS revealed the acid washes contained some product and the aqueousphase was concentrated in vacuo before extracting with ethyl acetate(3×15 mL). The combined ethyl acetate portions were washed with water(25 mL) and brine (25 mL) before drying through a hydrophobic frit andevaporating in vacuo to yield the crude product. The product was loadedin dichloromethane onto a 50 g SNAP silica cartridge and purified viaBiotage SP4 chromatography eluting from 15-60% ethylacetate/cyclohexane. The relevant fractions were evaporated in vacuo toyield a yellow gum. The flask was sonicated with ether and evaporatedonce more. The product was further dried in vacuo to yield the purifiedproduct—tert-butyl 4-(hydroxymethyl)-1H-benzo[d]imidazole-1-carboxylate(262 mg, 1.055 mmol, 78% yield) as a yellow gum.

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=249.0.

Intermediate 2: Methyl 1-tosyl-1H-indole-4-carboxylate

Methyl 1H-indole-4-carboxylate (750 mg, 4.28 mmol, commerciallyavailable from, for example, Sigma-Aldrich) was dissolved in DMF (13.591mL) at 0° C. under nitrogen. Sodium hydride (205 mg, 5.14 mmol, 60%dispersion in mineral oil) was added in portions. The reaction wasstirred at 0° C. for 10 min before warming to rt and stirring for 30min. Tosyl-Cl (979 mg, 5.14 mmol) was added and the reaction mixture wasstirred at rt for 10 min. The reaction was cooled to 0° C. and quenchedby the dropwise addition of water (3.86 mL, 214 mmol), before pouringonto saturated aqueous lithium chloride (140 mL). The product wasextracted with ethyl acetate (3×30 mL) and the combined organic portionswere dried through a hydrophobic frit and evaporated in vacuo to yieldthe crude product (2056 mg). The residue was dry loaded onto a 50 g SNAPsilica cartridge and purified via Biotage SP4 flash chromaotography,eluting from 0-25% ethyl acetate/cyclohexane. The relevant fractionswere combined and evaporated in vacuo to yield the pure product—methyl1-tosyl-1H-indole-4-carboxylate (1039 mg, 3.15 mmol, 73.7% yield) as awhite solid.

LCMS (2 min Formic): Rt=1.29 min, [MH]⁺=330.0.

Intermediate 3: (1-Tosyl-1H-indol-4-yl)methanol

A solution of methyl 1-tosyl-1H-indole-4-carboxylate (1016 mg, 3.08mmol) in DCM (30.361 mL) was cooled to −78° C. and DIBAL-H (1M intoluene, 13.57 mL, 13.57 mmol) was added dropwise over 1 h. The reactionmixture was stirred for a further 1.5 h, followed by a further 40 min.The reaction was quenched with methanol (0.125 mL, 3.08 mmol) when stillat −78° C. and then allowed to warm to ambient temperature. The reactionwas diluted with saturated Rochelle's salt solution (60 mL) and stirredfor 16 h. The layers were separated, and the aqueous phase was extractedwith dichloromethane (2×50 mL). The combined organic layers were driedthrough a hydrophobic frit and evaporated in vacuo to yield the crudeproduct (913 mg). The residue was loaded in dichloromethane onto a 50 gSNAP cartridge and purified via Biotage SP4, eluting from 15-75% ethylacetate/cyclohexane. The relevant fractions were combined and evaporatedin vacuo to yield the pure product—(1-tosyl-1H-indol-4-yl)methanol (901mg, 2.84 mmol, 92% yield) as a white solid.

LCMS (2 min Formic): Rt=1.07 min, [M+Na]⁺=324.0.

Intermediate 4: 4-(Bromomethyl)-1-tosyl-1H-indole

(1-Tosyl-1H-indol-4-yl)methanol (500 mg, 1.659 mmol) and HBr (3995 μL,48% in water, 33.2 mmol) were heated at 80° C. monitoring by LCMS.Initial LCMS indicated formation of product and the reaction was heatedfor a further 4 h. The reaction mixture was poured onto water (10 mL)and the product was extracted with dichloromethane (3×20 mL). Thecombined organic portions were dried through a hydrophobic frit andevaporated in vacuo to yield the crudeproduct—4-(bromomethyl)-1-tosyl-1H-indole (564 mg, 1.316 mmol, 79%yield) as a purple solid which was used without further purification.

LCMS (2 min Formic): Rt=1.35 min, [M−H]⁻=362.0, 364.0.

Intermediate 5: Methyl 1-tosyl-1H-indole-7-carboxylate

Methyl 1H-indole-7-carboxylate (1 g, 5.71 mmol, commercially availablefrom, for example, Apollo Scientific) was dissolved in DMF (18.12 mL) at0° C. under nitrogen. Sodium hydride (0.251 g, 60% dispersion in mineraloil, 6.28 mmol) was added in portions. The reaction was stirred at 0° C.for 10 min before warming to rt and stirring for 30 min. Tosyl-Cl (1.197g, 6.28 mmol) was added and the reaction mixture was stirred for 2 hr.The reaction was cooled back down to 0° C. and a further portion ofsodium hydride (0.114 g, 60% dispersion in mineral oil, 2.85 mmol) wasadded portionwise. The reaction mixture was stirred for 10 min beforewarming to rt and stirring for 30 min. An additional portion of tosyl-Cl(0.544 g, 2.85 mmol) was added at this point. The reaction was stirredfor a further 1.5 h. The reaction was quenched by the dropwise additionof water (5.14 mL, 285 mmol). The reaction was poured onto saturatedaqueous lithium chloride (100 mL) and the product was extracted withethyl acetate (3×30 mL). The combined organic portions were driedthrough a hydrophobic frit and evaporated in vacuo to yield the crudeproduct (2158 mg). The residue was dry loaded onto a 50 g SNAP silicacartridge and purified via Biotage SP4 flash chromatography, elutingfrom 0-25% ethyl acetate/cyclohexane. The relevant fractions werecombined and evaporated in vacuo to yield the pure product—methyl1-tosyl-1H-indole-7-carboxylate (1159 mg, 3.52 mmol, 61.6% yield) as ayellow solid.

LCMS (2 min Formic): Rt=1.18 min, [MH]⁺=330.0.

Intermediate 6: (1-Tosyl-1H-indol-7-yl)methanol

A solution of methyl 1-tosyl-1H-indole-7-carboxylate (1117 mg, 3.39mmol) in DCM (33.913 mL) was cooled to −78° C. and DIBAL-H (14.92 mL, 1Min toluene, 14.92 mmol) was added dropwise over 15 min. The reactionmixture was stirred for 1.5 h more. The reaction was quenched withmethanol (6.04 mL, 149 mmol) when still at −78° C. and then allowed towarm to ambient temperature. The reaction was diluted with Rochelle'ssalt solution (60 mL) and stirred for 16 h. The layers were separated,and the aqueous phase was extracted with dichloromethane (2×50 mL). Thecombined organic layers were dried through a hydrophobic frit andevaporated in vacuo to yield the crude product (1065 mg). The residuewas loaded in dichloromethane and purified via Biotage SP4, eluting from10-50% ethyl acetate/cyclohexane. The relevant fractions were combinedand evaporated in vacuo to yield a clear oil. The product was air driedto yield—(1-tosyl-1H-indol-7-yl)methanol (901 mg, 2.84 mmol, 84% yield).

LCMS (2 min Formic): Rt=1.07 min, [M−H]⁻=300.1.

Intermediate 7: 7-(Bromomethyl)-1-tosyl-1H-indole

(1-Tosyl-1H-indol-7-yl)methanol (500 mg, 1.659 mmol) and HBr (3995 μL,48% in water, 33.2 mmol) were heated at 80° C. for 1 h. The reactionmixture was filtered through a sinter funnel and washed with water. Thecollected precipitate was dissolved in dichloromethane (100 mL), driedthrough a hydrophobic frit and evaporated in vacuo to yield the crudeproduct—7-(bromomethyl)-1-tosyl-1H-indole (602 mg, 1.322 mmol, 80%yield) as a deep red oil which was used without further purification.

LCMS (2 min Formic): Rt=1.34 min, [MH]⁺=364.0, 366.0.

Intermediate 8: (1,2,3,4-Tetrahydroquinolin-8-yl)methanol

To 1,2,3,4-tetrahydroquinoline-8-carboxylic acid (500 mg, 2.82 mmol,commercially available from, for example, Fluorochem), boranetetrahydrofuran complex (8.47 mL, 1M in THF, 8.47 mmol) was added andthe reaction stirred at rt for 18 h. A further portion of boranetetrahydrofuran complex (2.82 mL, 1M in THF, 2.82 mmol) was added andstirring was continued for a further 3 h. The reaction was quenched withmethanol (10 mL, 247 mmol) and hydrochloric acid (10 mL, 1M, 10.00 mmol)and stirred for 2 h at rt. The reaction was concentrated in vacuo andtaken up in EtOAc (20 mL) and washed with NaHCO₃ (30 mL). The aqueouslayer was extracted with EtOAc (3×20 mL), the organic layers were washedwith brine (10 mL), dried over a hydrophobic frit and concentrated togive the crude product (ca. 450 mg) as an orange oil. The product wasloaded in dichloromethane onto a 25 g SNAP silica cartridge and purifiedvia Biotage SP4 flash chromatography, eluting from 15-75% ethylacetate/cyclohexane. The relevant fractions were combined and evaporatedin vacuo to yield the desiredproduct—(1,2,3,4-tetrahydroquinolin-8-yl)methanol (185 mg, 1.077 mmol,38.2% yield).

LCMS (2 min Formic): Rt=0.40 min, [MH]⁺=164.1.

Intermediate 9: 5-(Bromomethyl)quinoxaline

5-Methylquinoxaline (0.180 mL, 1.387 mmol, commercially available from,for example, Sigma-Aldrich), NBS (289 mg, 1.624 mmol), benzoyl peroxide(37 mg, 0.153 mmol) and 1,2-dichloroethane (4 mL) was stirred at 110° C.for 2 h. Further portions of NBS (260 mg, 1.461 mmol) and benzoylperoxide (31 mg, 0.128 mmol) were added and the reaction refluxed for afurther 2 h. The solution was concentrated to give 1.1 g of a brownsolid which was purified by chromatography on SiO₂ (Biotage SNAP 50 gcartridge, eluting with 0-100% diethylether/cyclohexane). The desiredfractions were concentrated to give 5-(bromomethyl)quinoxaline (310 mg,0.882 mmol, 63.6% yield) as a yellow oil.

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=223, 225.

Intermediate 10: 4-(Bromomethyl)-1H-indazole, hydrobromide

1H-Indazol-4-yl)methanol (202 mg, 1.363 mmol, commercially availablefrom, for example, Apollo Scientific) and HBr (3.3 mL, 48% in water,27.4 mmol) were heated at 80° C. for 2 h. The resulting suspension wasallowed to cool to rt, filtered under vacuum, washed with cold water anddried in a vacuum oven to give 4-(bromomethyl)-1H-indazole, hydrobromide(213 mg, 0.657 mmol, 48.2% yield) as an off white solid.

LCMS (2 min Formic): Rt=0.85 min, [MH]⁺=211, 213.

Intermediate 11: 7-(Bromomethyl)-1H-indazole, hydrobromide

(1H-Indazol-7-yl)methanol (250 mg, 1.687 mmol, commercially availablefrom, for example Fluorochem) and HBr (4 mL, 48% in water, 33.2 mmol)were heated at 80° C. for 1 h. The suspension was allowed to cool to rt,filtered under vacuum, washed with cold water and dried in a vacuum ovento give 7-(bromomethyl)-1H-indazole, hydrobromide (449 mg, 1.307 mmol,77% yield) as a white solid.

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=211, 213.

Intermediate 12: Methyl methyl 3-methyl-1H-indole-4-carboxylate

To 3-methyl-1H-indole-4-carboxylic acid (400 mg, 2.283 mmol,commercially available from, for example, Apollo Scientific) in methanol(20.757 mL) was added sulfuric acid (0.127 mL, 2.260 mmol) and thereaction was heated under reflux (65° C.) for 6 h. The reaction wascooled to ambient temperature and left to stand for 5 days. The reactionmixture was evaporated in vacuo and taken up in ethyl acetate (100 mL)and washed with water (2×10 mL), saturated sodium bicarbonate (10 mL)and brine (10 mL). The organic layer was dried through a hydrophobicfrit and evaporated in vacuo to yield the crude product as an orange oil(434 mg). The sample was loaded in DCM onto a 25 g SNAP cartridge andpurified via Biotage SP4 flash chromatography, eluting from 0-50%diethyl ether/cyclohexane. The relevant fractions were combined andevaporated in vacuo to isolate the pure product. The desired productmethyl 3-methyl-1H-indole-4-carboxylate (279 mg, 1.401 mmol, 61.4%yield) was obtained as a light green solid.

LCMS (2 min Formic): Rt=0.92 min, [MH]⁺=190.1.

Intermediate 13: Methyl 3-methyl-1-tosyl-1H-indole-4-carboxylate

Methyl 3-methyl-1H-indole-4-carboxylate (266 mg, 1.406 mmol) wasdissolved in DMF (3.515 mL) at 0° C. under nitrogen. Sodium hydride (60%dispersion in mineral oil) (73.1 mg, 1.828 mmol) was added in portions.The reaction was stirred at 0° C. for 10 min before warming to rt andstirring for 30 min. Tosyl-Cl (322 mg, 1.687 mmol) was added and thereaction mixture was stirred at rt for 15 min. The reaction was cooledto 0° C. and quenched by the careful addition of water (1 mL, 55.5mmol). Precipitation of the product was noted and the reaction mixturewas filtered, washing with water to retrieve a light green solid. Thesolid was dried in vacuo to yield the desired product—methyl3-methyl-1-tosyl-1H-indole-4-carboxylate (444 mg, 1.228 mmol, 87% yield)as a light green solid.

LCMS (2 min Formic): Rt=1.31 min, [MH]⁺=344.0.

Intermediate 14: (3-Methyl-1-tosyl-1H-indol-4-yl)methanol

A solution of methyl 3-methyl-1-tosyl-1H-indole-4-carboxylate (430 mg,1.252 mmol) in DCM (6.261 mL) under nitrogen, was cooled to −78° C. andDIBAL-H (2355 μL, 5.51 mmol, 2.34 M in toluene) was added drop-wise over30 min and the reaction was stirred at −78° C. for 2 h. The reaction wasquenched with methanol (1520 μL, 37.6 mmol) when still at −78° C. andafter allowed to warm to ambient temperature. The reaction was dilutedwith Rochelle's Salt solution (20 mL) and stirred for 16 h. The layerswere separated, and the aqueous phase was extracted with DCM (3×20 mL).The combined organic layers were dried through a hydrophobic frit, thenevaporated in vacuo to yield the crude product (481 mg). The sample wasloaded in DCM onto a SNAP cartridge (25 g) and purified via Biotage SP4flash chromatography, eluting from 10-62% ethyl acetate/cyclohexane. Thefractions were combined and evaporated in vacuo to yield the desiredproduct (3-methyl-1-tosyl-1H-indol-4-yl)methanol (311 mg, 0.966 mmol,77% yield) as a white solid.

LCMS (2 min Formic): Rt=1.12 min, Does not ionise at correct [MH]⁺.

Intermediate 15: tert-Butyl7-(hydroxymethyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

To3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-carboxylicacid (200 mg, 0.686 mmol, commerically available from, for example,Pharmablock), borane tetrahydrofuran complex (2.1 mL, 1M in THF, 2.100mmol) was added and the reaction stirred at rt under N₂ for 1 h. Thereaction mixture was diluted with EtOAc (10 mL) and washed with NaHCO₃(10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and thecombined organic layers were dried over a hydrophobic frit andconcentrated to give tert-butyl7-(hydroxymethyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (184mg, 0.597 mmol, 87% yield) as a colourless oil.

LCMS (2 min Formic): Rt=1.03 min, [M+Na]⁺=300.1.

Intermediate 16: (+/−)-1-(1-Bromoethyl)-3-methylbenzene

1-(m-Tolyl)ethanol (200 mg, 1.469 mmol, commercially available from, forexample, Alfa Aesar) was dissolved in DCM (5.9 mL) and stirred at 0° C.under N₂. PBr₃ (0.06 mL, 0.636 mmol) was added dropwise and the reactionstirred for 30 min at 0° C., then allowed to slowly warm to rt. Thesolution was quenched with sat. aq. sodium bicarbonate (20 mL), theaqueous layer was extracted with DCM (3×20 mL) and the combined organiclayers were dried over a hydrophobic frit and concentrated to give(+/−)-1-(1-bromoethyl)-3-methylbenzene (250 mg, 1.130 mmol, 77% yield)as a colourless oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.20-7.34 (m, 3H) 7.11 (d, J=7.3 Hz, 1H)5.44 (q, J=6.8 Hz, 1H) 2.31 (s, 3H) 1.97 (d, J=6.8 Hz, 3H).

Intermediate 17: (+/−)-1-(1-Bromoethyl)-2-methylbenzene

1-(o-Tolyl)ethanol (513 mg, 3.77 mmol, commercially available from, forexample, Alfa Aesar) was dissolved in DCM (5 mL) and stirred at 0° C.under N₂. PBr₃ (0.142 mL, 1.507 mmol) was added dropwise and thereaction stirred for 30 min at 0° C., then allowed to slowly warm to rt.A further portion of PBr₃ (0.355 mL, 3.77 mmol) was added dropwise at rtand the reaction stirred for 1.5 h. The solution was quenched with sat.aq. sodium bicarbonate (20 mL), the aqueous layer was extracted with DCM(3×20 mL) and the combined organic layers were dried over a hydrophobicfrit and concentrated to give (+/−)-1-(1-bromoethyl)-2-methylbenzene(670 mg, 2.69 mmol, 71.5% yield) as a colourless oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.54-7.60 (m, 1H) 7.15-7.27 (m, 3H) 5.62(q, J=6.8 Hz, 1H) 2.37 (s, 3H) 2.03 (d, J=6.8 Hz, 3H)

Intermediate 18: tert-Butyl5-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid(113 mg, 0.407 mmol, commercially available from, for example, ASWMedChem) in THF (1 mL), borane tetrahydrofuran complex (1.2 mL, 1M inTHF, 1.200 mmol) was added and the reaction stirred at rt for 1.5 h. Thereaction was diluted with EtOAc (10 mL) and washed with NaHCO₃ (10 mL).The aqueous layer was extracted with EtOAc (2×10 mL) and the organiclayers were dried over a hydrophobic frit and concentrated to give 600mg of a colourless oil. This was purified by chromatography on SiO₂(Biotage SNAP 50 g cartridge, eluting with 0-100% EtOAc/cyclohexane).The appropriate fractions were concentrated to give tert-butyl5-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (110 mg,0.376 mmol, 92% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.99 min, [MH-tBu]⁺=208.

Intermediate 19: 6-(Bromomethyl)-1H-benzo[d]imidazole

1H-Benzo[d]imidazol-6-yl)methanol (205 mg, 1.384 mmol, commerciallyavailable from, for example, Fluorochem) and HBr (3.4 mL, 48% in water,28.2 mmol) were heated at 80° C. for 30 min. The pH of the solution wasadjusted to pH 9 with sodium bicarbonate solution and extracted withEtOAc (2×20 mL). The combined organic layers were dried over ahydrophobic frit and concentrated to give6-(bromomethyl)-1H-benzo[d]imidazole (90 mg, 0.341 mmol, 24.66% yield)as a colourless oil.

¹H NMR (400 MHz, MeOH-d₄) δ ppm 8.24 (s, 1H) 7.55-7.67 (m, 2H) 7.30 (dd,J=8.3, 1.2 Hz, 1H) 4.73 (s, 2H).

Intermediate 20: tert-Butyl 4-(hydroxymethyl)indoline-1-carboxylate

Indolin-4-ylmethanol (301 mg, 2.018 mmol, commercially available from,for example, Fluorochem) was dissolved in DCM (5 mL), Boc-anhydride (660mg, 3.03 mmol) was added and the reaction stirred at rt under N₂ for 2h. The reaction was diluted with sat. aq. sodium bicarbonate (10 mL),extracted with DCM (2×10 mL), dried over a hydrophobic frit andconcentrated to give an orange oil (776 mg). This was purified bychromatography on SiO₂ (Biotage SNAP 50 g cartridge, eluting with 0-50%EtOAc/cyclohexane). The appropriate fractions were concentrated to givetert-butyl 4-(hydroxymethyl)indoline-1-carboxylate (472 mg, 1.704 mmol,84% yield) as a colourless oil.

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=194.1.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.52 (br. s., 1H) 7.12 (t, J=7.7 Hz, 1H)6.95 (d, J=7.6 Hz, 1H) 5.05 (t, J=5.5 Hz, 1H) 4.42 (d, J=5.4 Hz, 2H)3.91 (t, J=8.7 Hz, 2H) 3.00 (t, J=8.7 Hz, 2H) 1.50 (s, 9H).

Intermediate 21: Methyl 2-methyl-1H-benzo[d]imidazole-7-carboxylate

To 2-methyl-1H-benzo[d]imidazole-7-carboxylic acid (500 mg, 2.84 mmol,commercially available from, for example Fluorochem) in methanol (30mL), sulfuric acid (2.84 mL, 53.3 mmol) was added and the reactionstirred at 65° C. for 4 h. The reaction was then left to sit at rt for 3days. The reaction mixture was basified with aqueous ammonia at 65° C.The reaction mixture was extracted with DCM and concentrated undervacuum to give the title compound (410 mg, 2.156 mmol, 76% yield) as ayellow solid.

LCMS (2 min Formic): Rt=0.35 min, [MH]⁺=191.2.

Intermediate 22: (2-Methyl-1H-benzo[d]imidazol-7-yl)methanol

Under nitrogen, lithium borohydride (85 mg, 3.88 mmol) and methanol (4mL, 99 mmol) were dissolved in THF (20 mL). Then, methyl2-methyl-1H-benzo[d]imidazole-7-carboxylate (410 mg, 2.156 mmol) in THF(5 mL) was added to the mixture. The reaction was then stirred overnightat 50° C. under an inert atmosphere. The reaction mixture was quenchedwith water and 2M hydrochloric acid. The reaction mixture was thenpartitioned between water (50 mL) and ethyl acetate (50 mL). The aqueouslayer was then extracted with ethyl acetate (2×50 mL). The combinedorganic layers were passed through a hydriphobic frit and the solventwas removed under vacuum to give mainly unreacted SM. DIBAL-H (1.812 mL,25% in toluene, 2.69 mmol) was added dropwise to the crude recoveredsample (500 mg) in a solution of anhydrous DCM (20 mL) cooled to 0° C.The reaction was allowed to stir at 0° C. for 1 h under nitrogen.Further DIBAL-H (1.812 mL, 25% in toluene, 2.69 mmol) was added to thesolution and the reaction mixture was allowed to stir overnight.Methanol (4 mL, 99 mmol) was added slowly to the solution, followed byRochelle's salt solution (40 mL) and the mixture allowed to stir for 40min. The organic layer was separated and the aqueous layer extractedwith DCM (2×20 mL). The combined organics were washed with water (40 mL)followed by brine (40 mL). The organic layer was passed through ahydrophobic frit and concentrated under vacuum to give the titlecompound (250 mg, 1.541 mmol, 71.5%) as a white solid.

LCMS (2 min High pH): Rt=0.48 min, [MH]⁺=163.1.

Intermediate 23: tert-Butyl7-(hydroxymethyl)-2-methyl-1H-benzo[d]imidazole-1-carboxylate

To a solution of (2-methyl-1H-benzo[d]imidazol-7-yl)methanol (250 mg,1.541 mmol) in acetonitrile (11 mL) and water (2.75 mL) was added Boc₂O(0.501 mL, 2.158 mmol) and sodium bicarbonate (259 mg, 3.08 mmol). Themixture was stirred overnight at rt. The reaction mixture was dilutedwith ethyl acetate (70 mL) and washed with 10% aqueous citric acid (3×25mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). Thecombined ethyl acetate portions were washed with water (25 mL) and brine(25 mL) before drying through a hydrophobic frit and evaporating invacuo to yield the crude product. The product was loaded indichloromethane onto a SNAP cartridge (25 g) and purified via BiotageSP4 flash chromatography eluting from 0-100% ethyl acetate/cyclohexane.The relevant fractions were evaporated in vacuo to yield the titlecompound (128 mg, 0.488 mmol, 31.7% yield) as a white solid.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=263.1.

Intermediate 24: Benzofuran-4-ylmethanol

To benzofuran-4-carboxylic acid (50 mg, 0.308 mmol, commerciallyavailable from, for example, J&W PharmLab) in THF (1 mL), boranetetrahydrofuran complex (0.47 mL, 1M in THF, 0.470 mmol) was added andthe reaction stirred at rt for 1 h. The reaction was quenched withNaHCO₃ (20 mL) and extracted with EtOAc (3×10 mL). The organic layerswere dried over a hydrophobic frit and concentrated to give 50 mg of acolourless oil. This was purified by chromatography on SiO₂ (BiotageSNAP 10 g cartridge, eluting with 0-50% EtOAc/cyclohexane), theappropriate fractions were concentrated to give benzofuran-4-ylmethanol(37 mg, 0.225 mmol, 72.9% yield) as a white solid.

LCMS (2 min Formic): Rt=0.72 min, [M−OH]⁺=131.1.

Intermediate 25: 4-(Bromomethyl)benzofuran

Benzofuran-4-ylmethanol (35 mg, 0.236 mmol) was dissolved in diethylether (1 mL) and DCM (1 mL) at 0° C. under N₂. PBr₃ (0.04 mL, 0.424mmol) was added dropwise and the reaction was stirred at rt under N₂.After 30 min, TLC (eluting with 50:50 EtOAc:water) showed completeconversion to a non polar product. The solution was quenched with water(10 mL) and extracted with diethyl ether (3×20 mL), dried over ahydrophobic frit and concentrated to give 4-(bromomethyl)benzofuran (41mg, 0.117 mmol, 49.3% yield) as a white solid.

LCMS (2 min Formic): Rt=1.15 min, product does not ionise at correct[MH]⁺.

Intermediate 26: 1-(1-Tosyl-1H-indol-4-yl)ethanone

1-(1H-Indol-4-yl)ethanone (505 mg, 3.17 mmol, commercially availablefrom, for example, Activate Scientific) was dissolved in DMF (5 mL) at0° C. under N₂. Sodium hydride (167 mg, 4.18 mmol, 60% in mineral oil)was added in portions. The reaction was stirred at 0° C. for 10 minbefore warming to rt and stirring for 30 min. Tosyl-Cl (726 mg, 3.81mmol) was added and the reaction mixture was stirred at rt for 30 min.Further sodium hydride (140 mg, 3.50 mmol, 60% in mineral oil) was addedand the reaction stirred for 10 min, then tosyl-Cl (721 mg, 3.78 mmol)was added and the reaction stirred for 20 min. The reaction was quenchedwith water (20 mL) and left to stand overnight. This was extracted withEtOAc (2×20 mL), dried over a hydrophobic frit and concentrated to give1.33 g of a brown solid. This was purified by chromatography on SiO₂(Biotage SNAP 25 g cartridge, eluting with 0-50% EtOAc/cyclohexane). Theappropriate fractions were concentrated to give1-(1-tosyl-1H-indol-4-yl)ethanone (899 mg, 2.58 mmol, 81% yield) as ayellow solid.

LCMS (2 min Formic): Rt=1.23 min, [MH]⁺=314.0.

Intermediate 27: (+/−)-1-(1-Tosyl-1H-indol-4-yl)ethanol

1-(1-Tosyl-1H-indol-4-yl)ethanone (899 mg, 2.87 mmol) was dissolved inmethanol (9 mL) at 0° C. under N₂. Sodium borohydride (170 mg, 4.49mmol) was added and the reaction allowed to warm to rt. After stirringfor 1.5 h, further sodium borohydride (121 mg, 3.20 mmol) was added andthe reaction was stirred overnight. The solution was concentrated togive an orange solid. This was partitioned between EtOAc (20 mL) andwater (20 mL), extracted with EtOAc (2×20 mL), dried over a hydrophobicfrit and concentrated to give 1.05 g crude product as an orange oil.This was purified by chromatography on SiO₂ (Biotage SNAP 25 gcartridge, eluting with 0-50% EtOAc/cyclohexane). The appropriatefractions were concentrated to give 1-(1-tosyl-1H-indol-4-yl)ethanol(862 mg, 2.460 mmol, 86% yield) as a yellow oil.

LCMS (2 min Formic): Rt=1.12 min, [M−H]⁻=314.1.

Intermediate 28: (+/−)-4-(1-Bromoethyl)-1-tosyl-1H-indole

1-(1-Tosyl-1H-indol-4-yl)ethanol (160 mg, 0.507 mmol) was dissolved indiethyl ether (1 mL) and DCM (1 mL) at 0° C. under N₂. PBr₃ (0.07 mL,0.742 mmol) was added dropwise and the reaction was stirred at rt underN₂ for 2 h. Further PBr₃ (0.07 mL, 0.742 mmol) was added and thereaction stirred for 3 h. Further PBr₃ (0.07 mL, 0.742 mmol) was addedand the reaction stirred for 2 h. The reaction was quenched with water(20 mL), extracted with Et₂O (2×20 mL), dried over a hydrophobic fritand concentrated to give 4-(1-bromoethyl)-1-tosyl-1H-indole (275 mg,0.509 mmol, 100% yield) as a pink solid which was used crude in furthersynthesis.

LCMS (2 min Formic): Rt=1.32 min, product does not ionise at correct[MH]⁺.

Intermediate 29: 5-(Bromomethyl)-2-methoxypyridine

(6-Methoxypyridin-3-yl)methanol (250 mg, 1.797 mmol, commerciallyavailable from, for example, Fluorochem) was dissolved in chloroform (20mL) in a 50 mL round-bottomed flask, open to the atmosphere andphosphorus tribromide (0.188 mL, 1.989 mmol) was added slowly at 0° C.The reaction mixture was stirred at rt for 1 h. The aqueous layer wasextracted with DCM (3×30 mL) and the organic layers were combined,washed with brine (30 mL), passed through a hydrophobic frit andevaporated under vacuum. The resulting oil was loaded in DCM andpurified by Biotage Isolera SNAP 25 g silica chromatography using agradient of 0-40% cyclohexane/ethyl acetate. The product containingfractions were combined to give the title compound (160 mg, 0.792 mmol,44.1% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.93 min, [MH]⁺=202.

Intermediate 30: 2,4,6-Trichlorophenyl Formate

Formic acid (57.3 mL, 1519 mmol) and acetic anhydride (115 mL, 1216mmol) were stirred and heated to 60° C. for 1.5 h then allowed to coolto ambient temperature. The resulting solution was poured into a flaskcontaining 2,4,6-trichlorophenol (30 g, 152 mmol, commercially availablefrom, for example, Sigma-Aldrich) and sodium acetate (12.46 g, 152mmol). The mixture was stirred for 3.5 h, diluted with toluene (300 mL),washed with water (2×200 mL), dried with sodium sulphate, filtered andevaporated to dryness in vacuo to afford white needle-like crystals(32.45 g).

LCMS (2 min Formic): Rt=1.15 min, [M+Na]⁺=249.8.

Intermediate 31: tert-Butyl ((1S,2S)-2-methylcyclopropyl)carbamate

(1S,2S)-2-Methylcyclopropanecarboxylic acid (200 mg, 1.998 mmol,commercially available from, for example, Enamine) and triethylamine(0.9 mL, 6.46 mmol) were dissolved in tert-butanol (4 mL). Diphenylphosphorylazide (0.47 mL, 2.181 mmol) was added and the reaction washeated at 90° C. The reaction was followed by TLC (eluting with 50:50EtOAc:cyclohexane, visualising with Ninhydrin). After 2 h, TLC showedthe formation of a less polar product as well as residual SM. Thereaction was stirred for 3 days. The solution was partitioned betweenEtOAc (10 mL), and sodium bicarbonate solution. (10 mL), extracted withEtOAc (2×20 mL), dried over a hydrophobic frit and concentrated to give1.08 g of a yellow solid. This was purified by chromatography on SiO₂(Biotage SNAP 25 g cartridge, eluting with 0-50% EtOAc/cyclohexane). Theappropriate fractions were concentrated to give tert-butyl((1S,2S)-2-methylcyclopropyl)carbamate (223 mg, 1.172 mmol, 58.7% yield)as a white crystalline solid.

¹H NMR (400 MHz, MeOH-d₄) δ ppm 2.05-2.14 (m, 1H) 1.43 (br. s., 9H) 1.04(d, J=5.9 Hz, 3H) 0.78 (m, J=8.9, 6.0, 6.0, 3.1 Hz, 1H) 0.59 (dt, J=8.9,4.3 Hz, 1H) 0.39 (q, J=6.0 Hz, 1H).

Intermediate 32: (1S,2S)-2-Methylcyclopropanamine hydrochloride

tert-Butyl ((1S,2S)-2-methylcyclopropyl)carbamate (215 mg, 1.256 mmol)was stirred in 4 M HCl in dioxane (16 mL, 64.0 mmol). The reaction wasfollowed by TLC (50:50 EtOAc:cyclohexane, visualising with Ninhydrin).After 30 min, the solution was concentrated to give(1S,2S)-2-methylcyclopropanamine hydrochloride (151 mg, 1.123 mmol, 89%yield) as an off white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (br. s., 3H) 2.25 (br. s., 1H)1.06-1.18 (m, 1H) 0.99 (d, J=6.1 Hz, 3H) 0.85 (ddd, J=9.4, 5.6, 3.8 Hz,1H) 0.48 (dt, J=7.5, 5.9 Hz, 1H).

Intermediate 33: Methyl1-benzyl-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate

Sodium hydride (5.17 g, 60% dispersion in mineral oil, 129 mmol) wasadded to a solution of methyl5-bromo-2-oxo-1,2-dihydro-3-pyridinecarboxylate (25 g, 108 mmol,commercially available from, for example, Fluorochem) in DMF (200 mL)and THF (200 mL) at 0° C. and the mixture was stirred for 30 min, givinga dense suspension. Benzyl bromide (14.10 mL, 119 mmol) was added andthe mixture stirred for a further 2 h, allowing to warm to rt, then theresulting clear brown solution was added to water (400 mL) and extractedwith EtOAc (2×300 mL). The combined organics were washed with water(2×200 mL), dried and evaporated in vacuo to give methyl1-benzyl-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (31 g, 96 mmol,89% yield) as a beige solid. This material was carried through to thenext step without purification.

LCMS (2 min High pH): Rt=0.98 min, [MH]⁺=322.0 & 324.1.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 8.16 (d, J=2.9 Hz, 1H) 7.62 (d, J=2.9Hz, 1H) 7.30-7.43 (m, 5H) 5.15 (s, 2H) 3.92 (s, 3H).

Intermediate 34: 1-Benzyl-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylicacid

Lithium hydroxide (6.91 g, 289 mmol) in water (200 mL) was added to amixture of methyl1-benzyl-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (31 g, 96mmol), THF (200 mL) and methanol (200 mL) and the mixture was stirred atrt for 2 h, then evaporated in vacuo to about half volume, giving adense suspension. This was diluted with water (200 mL) and acidifiedwith acetic acid to pH 5, then extracted with EtOAc (2×300 mL). Thecombined organics were dried over sodium sulphate and evaporated invacuo to give an off-white solid. The product was suspended in ether(200 mL), sonicated, diluted with cyclohexane (100 mL) and collected byfiltration to give1-benzyl-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (23 g, 74.6mmol, 78% yield).

LCMS (2 min Formic): Rt=1.01 min, [MH]⁺=308.0 & 310.1.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 14.02 (br. s., 1H) 8.55 (d, J=2.7 Hz,1H) 7.73 (d, J=2.7 Hz, 1H) 7.40-7.47 (m, 3H) 7.31-7.37 (m, 2H) 5.25 (s,2H).

Intermediate 35:1-Benzyl-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

1-Benzyl-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (28 g, 91mmol) was suspended in DCM (300 mL) and oxalyl chloride (23.86 mL, 273mmol) and DMF (0.352 mL, 4.54 mmol) were added, then the mixture wasstirred for 2 h at rt. The solvent was evaporated in vacuo to give abrown residue, which was then dissolved in THF (300 mL) and Et₃N (12.67mL, 91 mmol) was added. The mixture was cooled in an ice bath, thenmethanamine (91 mL, 2M in THF, 182 mmol) was added dropwise over 30 minand the mixture stirred for a further 1 h at 0° C. The solvent wasevaporated in vacuo and the solid residue was partitioned between water(300 mL) and DCM (300 mL), the organic layer was washed with brine,dried and evaporated in vacuo to give1-benzyl-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (27.6g, 86 mmol, 95% yield) as a brown solid.

LCMS (2 min Formic): Rt=0.97 min, [MH]⁺=321.0 & 323.1.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 9.57 (br. s., 1H) 8.60 (d, J=2.9 Hz, 1H)7.62 (d, J=2.9 Hz, 1H) 7.34-7.48 (m, 3H) 7.29-7.33 (m, 2H) 5.20 (s, 2H)3.00 (d, J=4.9 Hz, 3H).

Intermediate 36: Ethyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

1-Benzyl-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (23 g,71.6 mmol), DMSO (60 mL), ethanol (70 g, 1519 mmol), Et₃N (19.96 mL, 143mmol), dppb (3.05 g, 7.16 mmol) and palladium acetate (1.608 g, 7.16mmol) were placed in a steel Parr vessel, which was then purged withcarbon monoxide by filling to 50 psi, then releasing the pressure, thenrefilled to 50 psi and heated overnight at 100° C. The mixture wasdiluted with water (200 mL) and extracted with EtOAc (2×300 mL), theorganic layer washed with water (2×300 mL), then dried and evaporated invacuo and the residue was triturated with ether (200 mL) and the solidcollected by filtration to give ethyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(21.2 g, 67.4 mmol, 94% yield).

LCMS (2 min Formic): Rt=0.99 min, [MH]⁺=315.2.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 9.37 (br. s., 1H) 9.03 (d, J=2.4 Hz, 1H)8.38 (d, J=2.7 Hz, 1H) 7.34-7.42 (m, 3H) 7.28-7.34 (m, 2H) 5.25 (s, 2H)4.35 (q, J=7.1 Hz, 2H) 2.99 (d, J=4.9 Hz, 3H) 1.37 (t, J=7.2 Hz, 3H).

Intermediate 37:1-Benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid

Sodium hydroxide (99 mL, 199 mmol) was added to a solution of ethyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(20.8 g, 66.2 mmol) in a mixture of methanol (100 mL) and THF (100 mL)and the resulting solution was stirred for 2 h at rt, then evaporated invacuo to approximately 100 mL volume. The mixture was diluted with water(200 mL), then filtered to remove a dark grey solid, the filtrate waswashed with MTBE (200 mL), then acidified to pH 4 with 2M HCl and theresulting suspension stirred for 2 h, then filtered and the productwashed with water, then dried in the vacuum oven to give1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(15.2 g, 53.1 mmol, 80% yield).

LCMS (2 min High pH): Rt=0.58 min, [MH]⁺=287.2.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.19 (br. s., 1H) 9.14-9.34 (m, 1H)8.88 (d, J=2.7 Hz, 1H) 8.70 (d, J=2.7 Hz, 1H) 7.25-7.42 (m, 5H) 5.33 (s,2H) 2.82 (d, J=4.6 Hz, 3H).

Intermediate 38: Methyl 2-(benzyloxy)-5-bromonicotinate

Methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (5 g, 21.55 mmol,commercially available from, for example, Sigma-Aldrich) was dissolvedin chloroform (100 mL), then silver carbonate (11.88 g, 43.1 mmol) andbenzyl bromide (3.33 mL, 28.0 mmol) were added and the mixture heated atreflux overnight. The mixture was filtered and the filtrate evaporatedin vacuo to give a pale yellow liquid. This was dissolved in DCM (5 mL)and loaded onto a 50 g silica column, then eluted with 0-50%EtOAc/cyclohexane and the product-containing fractions evaporated invacuo to give methyl 2-(benzyloxy)-5-bromonicotinate (4.65 g, 14.43mmol, 67.0% yield) as a colourless solid

LCMS (2 min High pH): Rt=1.37 min, [MH]⁺=322.1, 324.1.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 8.35 (d, J=2.7 Hz, 1H) 8.29 (d, J=2.4Hz, 1H) 7.51 (d, J=7.6 Hz, 2H) 7.38 (t, J=7.5 Hz, 2H) 7.28-7.34 (m, 1H)5.51 (s, 2H) 3.93 (s, 3H).

Intermediate 39: (R)-Methyl2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxylate

(R)-1-Phenylethanamine (8.93 mL, 70.2 mmol) was added to a stirredsolution of methyl 2-oxo-2H-pyran-3-carboxylate (10.3 g, 66.8 mmol,commercially available from, for example, Sigma-Aldrich) in a mixture ofdry DMF (43 mL) and dry THF (173 mL). The resulting dark red solutionwas stirred for 30 min, under N₂. EDC (16.66 g, 87 mmol) and DMAP (0.506g, 4.14 mmol) were added and the resulting suspension stirred over theweekend. The reaction mixture was evaporated in vacuo to a brown slurry.The residue was partitioned between EtOAc and water and the aqueouslayer removed. The organic layer was washed (3×2 M aq. HCl, 1× brine),dried over MgSO₄ and filtered through silica eluting with EtOAc. Thefiltrate was evaporated in vacuo to give the product as a brown oil(12.94 g).

LCMS (2 min TFA): Rt=0.84 min, [MH]⁺=258.1.

Intermediate 40: (R)-Methyl5-bromo-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxylate

NBS (10.74 g, 60.4 mmol) was added in one portion to a dark brownsolution of (R)-methyl2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxylate (12.94 g, 50.3mmol) in 2-MeTHF (150 mL). The initial suspension became a light brownsolution and was stirred for 15 min whereupon it was a dark brownsolution. The reaction mixture was washed [3× sat. aq. NaHCO₃ (40 mL),1× aq. 10% sodium thiosulfate (20 mL), 1× brine (10 mL)], dried overMgSO₄ and evaporated in vacuo to a black oil. The residue was dissolvedin toluene (40 mL), filtered through celite, washing with toluene (80mL) and evaporated in vacuo to give the product (19.62 g) as a blackoil.

LCMS (2 min TFA): Rt=1.02 min, [MH]⁺=336.0 & 337.9.

Intermediate 41:(R)-5-Bromo-N-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxamide

Methylamine solution (74 mL, 40% aq., 855 mmol) was added to a solutionof (R)-methyl5-bromo-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxylate (19.2g, 40.0 mmol) in methanol (133 mL). The resulting solution was heated to50° C. with a balloon fitted to the top of a condensor. The reactionmixture was stirred for 90 min. The reaction mixture was evaporated invacuo to a black gum that was suspended in EtOAc. The suspension wasfiltered through silica eluting with EtOAc and the filtrate evaporatedto give the product (13.1 g) as a brown gum.

LCMS (2 min TFA): Rt=1.01 min, [MH]⁺=335.1 & 337.1

Intermediate 42: (R)-Methyl5-(methylcarbamoyl)-6-oxo-1-(1-phenylethyl)-1,6-dihydropyridine-3-carboxylate

Xantphos (1.65 g, 2.85 mmol) and palladium(II) acetate (0.877 g, 3.91mmol) were added to a solution of(R)-5-bromo-N-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxamide(13.1 g, 39.1 mmol), triethylamine (16.34 mL, 117 mmol) and methanol(15.81 mL, 391 mmol) in DMF (220 mL). Carbon monoxide was spargedthrough the mixture until a brown suspension formed. The reaction washeld under a balloon of carbon monoxide and heated to 60° C. for 4 h.The reaction mixture was cooled to rt and sparged with N₂ to remove anyresidual carbon monoxide. The reaction mixture was filtered throughcelite, rinsing with EtOAc and the filtrate evaporated in vacuo to ablack slurry. The residue was partitioned between EtOAc (350 mL) andwater (100 mL). The aqueous layer was removed, the organic layer washed(2× water [50 mL], 1× brine [50 mL]), dried over MgSO₄ and evaporated invacuo to a black gum. The gum was dissolved in toluene (60 mL) andloaded on to a Biotage 340 g silica column. The column was eluted withcyclohexane:EtOAc (20→66%). The product containing fractions wereevaporated to give the product (7.43 g) as a brown gum.

LCMS (2 min TFA): Rt=0.94 min, [MH]⁺=315.2.

Intermediate 43:(R)-5-(Methylcarbamoyl)-6-oxo-1-(1-phenylethyl)-1,6-dihydropyridine-3-carboxylicacid

Sodium hydroxide (1.891 g, 47.3 mmol) was added to a solution of(R)-methyl5-(methylcarbamoyl)-6-oxo-1-(1-phenylethyl)-1,6-dihydropyridine-3-carboxylate(7.43 g, 23.64 mmol) in methanol (70 mL). Water was added to the stirredsuspension and the resulting solution stirred overnight. The reactionmixture was evaporated in vacuo to a pale brown solid and acidified with2M aq. HCl (100 mL). Acetone (10 mL) was added and the suspensionstirred for 15 min and filtered. The filtercake was washed[water:acetone (1:1, 20 mL), acetone (20 mL)] and dried in vacuo to givethe product (6.40 g) as a beige solid.

LCMS (2 min TFA): Rt=0.82 min, [MH]⁺=301.0.

Intermediate 44: (S*)-Methyl5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate

Methyl 5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (700mg, 3.33 mmol), 1-(1-bromoethyl)-3-methylbenzene (800 mg, 4.02 mmol),potassium carbonate (1310 mg, 9.48 mmol) and DMF (5 mL) were stirred at90° C. for 1 h. The suspension was concentrated, partitioned betweenEtOAc (20 mL) and water (20 mL), the aqueous phase was extracted withEtOAc (2×20 mL), dried over a hydrophobic frit and concentrated to give1.2 g of an orange oil. This was purified by chromatography on SiO₂(Biotage SNAP 50 g cartridge, eluting with 0-100% (25% EtOH inEtOAc)/cyclohexane). The appropriate fractions were concentrated to give(+/−)-methyl5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate(710 mg, 1.946 mmol, 58.4% yield) as a white solid. 677 mg of theracemate was submitted for chiral separation:

Analytical Method:

The racemate (˜0.5 mg) was dissolved in 50% EtOH/Heptane (1 mL). 20 μLwas injected on the column. (Column: 4.6 mmid×25 cm Chiralpak IA, LotNo. IA00CE-MC024). This was eluted with 50% EtOH/Heptane, f=1.0 mL/min,detector wavelength 215 nm, 4. Ref 550,100

Prep Method:

The racemate (˜80 mg) was dissolved in DCM (1 mL) and EtOH (2 mL). 3 mLof the solution was injected onto the column. (Column: 30 mm×25 cmChirapak IA (5 μm), Lot No IA11157-01). This was eluted with 50%EtOH/Heptane, f=30 mL/min, detector wavelength=215 nm, 4. Ref 550,100

There were a total of 14 injections. Fractions from 7-8 min were bulkedand labelled peak 1, fractions from 8-9 min were bulked and labelledmix, fractions from 9-12 min were bulked and labelled peak 2. The bulkedmix fractions were vac'ed down and reprocessed using the the prep methodabove. The bulked fractions were vac'ed down using a rotary evaporatorand then transferred to a weighed flask for final analysis as describedby the analytical method above.

First eluting isomer: (9S)-methyl5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate(289 mg, 0.792 mmol, 23.78% yield) was obtained as a colourless oil.

LCMS (2 min Formic): Rt=1.05 min, [M−H]⁻=329.1.

Intermediate 45:(S*)-5-(Methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylicacid

(S*)-Methyl5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate(289 mg, 0.880 mmol), lithium hydroxide (66 mg, 2.76 mmol), 1,4-dioxane(3 mL) and water (3 mL) were stirred at rt for 30 min. The solution wasacidified to pH 4 with acetic acid (0.050 mL, 0.880 mmol), thenpartitioned between EtOAc (20 mL) and water (20 mL), extracted withEtOAc (20 mL), dried over a hydrophobic frit and concentrated to give(*)-5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylicacid (277 mg, 0.705 mmol, 80% yield).

LCMS (2 min Formic): Rt=0.94 min, [M−H]⁻=313.2.

Intermediate 46: Methyl5-bromo-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxylate

(1-Bromoethyl)benzene (0.706 mL, 5.17 mmol) was added to a stirredsuspension of methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate(1.0 g, 4.31 mmol) and potassium carbonate (0.715 g, 5.17 mmol) in DMF(10 mL). The white suspension was stirred overnight. The reactionmixture was partitioned between EtOAc and water. The aqueous layer wasremoved, the organic layer washed (2× water), dried over MgSO₄ andevaporated in vacuo to a colourless oil. The residue was dissolved inDCM, loaded on to a 25 g Biotage silica SNAP column and eluted withcyclohexane:EtOAc (5→40%). The product containing fractions wereevaporated in vacuo to give the product (824 mg) as a colourless oil.

LCMS (2 min TFA): Rt=1.02 min, [MH]⁺=335.9 & 337.9.

Intermediate 47:5-Bromo-N-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxamide

Methylamine solution (3.167 mL, 40% aq., 36.6 mmol) was added to asolution of methyl5-bromo-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxylate (820mg, 2.439 mmol) in methanol (8 mL). The resulting solution was heated to50° C. in a sealed system with a balloon fitted for 4 h. The reactionmixture was evaporated in vacuo to give the product (793 mg) as acolourless gum.

LCMS (2 min TFA): Rt=1.01 min, [MH]⁺=335.0 & 337.0.

Intermediate 48: 2-(Benzyloxy)-5-bromonicotinic acid

Methyl 2-(benzyloxy)-5-bromonicotinate (4.6 g, 14.28 mmol) was dissolvedin THF (50 mL) and methanol (50 mL), then LiOH (1.368 g, 57.1 mmol) inwater (50 mL) was added and the mixture stirred for 2 h at rt. Thesolvent was evaporated in vacuo and the residue was suspended in water(100 mL) and acidified with 2M HCl to pH 4, then extracted with 10%MeOH/DCM (3×100 mL, poor solubility) and the organic layer washed withwater, dried and evaporated in vacuo to give2-(benzyloxy)-5-bromonicotinic acid (4.15 g, 13.47 mmol, 94% yield) as acolourless solid.

LCMS (2 min High pH): Rt=0.68 min, [MH]⁺=308.2, 310.0.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.43 (d, J=2.4 Hz, 1H) 8.18 (d, J=2.7Hz, 1H) 7.47 (d, J=7.1 Hz, 2H) 7.37 (t, J=7.3 Hz, 2H) 7.27-7.33 (m, 1H)5.43 (s, 2H).

Intermediate 49: 2-(Benzyloxy)-5-bromo-N-methylnicotinamide

2-(Benzyloxy)-5-bromonicotinic acid (4.2 g, 13.63 mmol) was suspended inDCM (50 mL) and oxalyl chloride (2.386 mL, 27.3 mmol) was added,followed by DMF (0.053 mL, 0.682 mmol) and the reaction mixture wasstirred for 2 h at rt, then evaporated in vacuo. The residue wasdissolved in THF (50 mL), then methanamine (13.63 mL, 2M in THF, 27.3mmol) was added and the resulting suspension stirred for 2 h at rt, thenevaporated in vacuo. The residue was dissolved in THF (50 mL) andmethanamine (13.63 mL, 2M in THF, 27.3 mmol) was added, then theresulting mixture stirred for 2 h, then evaporated in vacuo. The residuewas partitioned between EtOAc (100 mL) and water (100 mL), the aq. layerwas extracted with further EtOAc (100 mL) and the combined organicswashed with brine, dried and evaporated in vacuo to give a yellow gummysolid. This was dissolved in a mixture of DCM (20 mL) and methanol (5mL) with difficulty, then loaded onto a 50 g silica column, which wasthen sucked dry using a vacuum line. The column was eluted with 0-100%EtOAc/cyclohexane to give 2-(benzyloxy)-5-bromo-N-methylnicotinamide(2.35 g, 7.32 mmol, 53.7% yield)

LCMS (2 min High pH): Rt=1.19 min, [MH]⁺=321.1, 323.1.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 8.65 (d, J=2.4 Hz, 1H) 8.31 (d, J=2.4Hz, 1H) 7.87 (br. s., 1H) 7.33-7.48 (m, 5H) 5.53 (s, 2H) 2.94 (d, J=4.9Hz, 3H).

Intermediate 50: 2,4,6-Trichlorophenyl6-(benzyloxy)-5-(methylcarbamoyl)nicotinate

2-(Benzyloxy)-5-bromo-N-methylnicotinamide (2 g, 6.23 mmol), Xantphos(0.721 g, 1.245 mmol), palladium acetate (0.140 g, 0.623 mmol) and Et₃N(1.302 mL, 9.34 mmol) were combined in a three necked flask equippedwith a dropping funnel and a condensor with a nitrogen bubbler on thetop. Toluene (30 mL) was added and the mixture was heated at 80° C.under nitrogen for 20 min, then a solution of 2,4,6-trichlorophenylformate (2.106 g, 9.34 mmol) in toluene (20 mL) was added dropwise over30 min and heating continued for 18 h.

Separately, 2-(benzyloxy)-5-bromo-N-methylnicotinamide (0.6 g, 1.868mmol), Xantphos (0.216 g, 0.374 mmol), palladium acetate (0.042 g, 0.187mmol) and Et₃N (0.391 mL, 2.80 mmol) were combined in a three neckedflask equipped with a dropping funnel and a condensor with a nitrogenbubbler on the top. Toluene (30 mL) was added and the mixture was heatedat 80° C. under nitrogen for 20 min, then a solution of2,4,6-trichlorophenyl formate (0.632 g, 2.80 mmol) in toluene (20 mL)was added dropwise over 30 min and heating continued for 2 h.

The two separate reactions were combined and diluted with EtOAc (100 mL)and washed with water (50 mL) and brine (50 mL), dried and evaporated invacuo to give an orange oil. This was dissolved in DCM (10 mL) andloaded onto a 50 g silica column, then eluted with 0-50%EtOAc/cyclohexane and the product-containing fractions evaporated invacuo to give a beige solid. The product was columned again on a 50 gsilica cartridge eluting with 0-50% EtOAc/cyclohexane, and the purefractions collected and evaporated in vacuo to give2,4,6-trichlorophenyl 6-(benzyloxy)-5-(methylcarbamoyl)nicotinate (1.65g, 3.54 mmol, 56.9% yield).

LCMS (2 min High pH): Rt=1.52 min, [MH]⁺=465.3.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 9.31 (d, J=2.4 Hz, 1H) 9.10 (d, J=2.4Hz, 1H) 7.80 (d, J=3.7 Hz, 1H) 7.38-7.53 (m, 7H) 5.68 (s, 2H) 2.98 (d,J=4.6 Hz, 3H).

Intermediate 51: 2-(Benzyloxy)-N5-cyclobutyl-N3-methylpyridine-3,5-dicarboxamide

2,4,6-Trichlorophenyl 6-(benzyloxy)-5-(methylcarbamoyl)nicotinate (1.65g, 3.54 mmol) was dissolved in THF (20 mL) and Et₃N (0.988 mL, 7.09mmol) was added. Cyclobutanamine (0.605 mL, 7.09 mmol) and DMAP (0.022g, 0.177 mmol) were added and the reaction mixture heated at 45° C. for15 min. The reaction was heated for a further 30 min, then allowed tocool and concentrated in vacuo. The crude colourless oil was thenpartitioned between ethyl acetate (30 mL) and water (30 mL). The productwas extracted with ethyl acetate (2×30 mL) and the combined ethylacetate layers were dried (Na₂SO₄) and evaporated in vacuo. The cruderesidue was loaded in dichloromethane and purified via Biotage SP4 flashchromatography eluting from 20-100% ethyl acetate/cyclohexane. Therelevant fractions were combined and evaporated in vacuo to yield theproduct—2-(benzyloxy)-N5-cyclobutyl-N3-methylpyridine-3,5-dicarboxamide(1.025 g, 3.02 mmol, 85% yield) as a white solid.

LCMS (2 min Formic): Rt=1.01 min, [MH]⁺=340.0.

Intermediate 52:N5-Cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

TFA (2 mL, 26.0 mmol) was added to2-(benzyloxy)-N5-cyclobutyl-N3-methylpyridine-3,5-dicarboxamide (1.18 g,3.48 mmol) and the mixture was heated at 80° C. for 1 h and then afurther 20 min and then allowed to cool and evaporated in vacuo to givea grey solid. The crude product was triturated with ether (5 mL) and theproduct collected by filtration to giveN5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (718mg, 2.88 mmol, 83% yield) as a white solid.

LCMS (2 min Formic): Rt=0.55 min, [MH]⁺=250.0.

Intermediate 53:2-(Benzyloxy)-N5-cyclopropyl-N3-methylpyridine-3,5-dicarboxamide

The reactants, 2,4,6-trichlorophenyl6-(benzyloxy)-5-(methylcarbamoyl)nicotinate (771 mg, 1.656 mmol),cyclopropanamine (327 mg, 5.73 mmol), Et₃N (461 μL, 3.31 mmol) and DMAP(10.11 mg, 0.083 mmol) were combined in 2-methyltetrahydrofuran (20 mL)and heated to 45° C. overnight and the reaction was then cooled andconcentrated in vacuo. The crude product was applied to a 50 g SNAPsilica cartridge in the minimum of DCM and eluted with 5-50% (3:1EtOAc:EtOH) in cyclohexane. The appropriate fractions were concentratedin vacuo to give2-(benzyloxy)-N5-cyclopropyl-N3-methylpyridine-3,5-dicarboxamide (485.2mg, 1.417 mmol, 86% yield) as a cream solid.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=326.3.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 8.88 (d, J=2.7 Hz, 1H) 8.72 (d, J=2.4Hz, 1H) 7.88 (br. s., 1H) 7.32-7.50 (m, 5H) 6.40 (br. s., 1H) 5.62 (s,2H) 2.87-2.99 (m, 4H) 0.82-0.95 (m, 2H) 0.57-0.70 (m, 2H).

Intermediate 54:N5-Cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2-(Benzyloxy)-N5-cyclopropyl-N3-methylpyridine-3,5-dicarboxamide (485mg, 1.491 mmol) was taken up in TFA (5 mL, 64.9 mmol) and heated to 90°C. for 3 h and the reaction was concentrated in vacuo. The residue wasstirred in Et₂O (20 mL) for 30 min and then left to stand over theweekend. The resulting precipitate was collected by filtration to giveN5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(364.9 mg, 1.474 mmol, 99% yield) as a cream solid.

LCMS (2 min Formic): Rt=0.45 min, [MH]⁺=236.2.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.79 (br. s., 1H) 9.41 (d, J=4.9 Hz,1H) 8.76 (d, J=2.7 Hz, 1H) 8.44 (d, J=3.7 Hz, 1H) 8.19 (d, J=2.7 Hz, 1H)2.76-2.87 (m, 4H) 0.64-0.71 (m, 2H) 0.51-0.57 (m, 2H).

Intermediate 55: tert-Butyl4-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate

N5-Cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(192 mg, 0.815 mmol), tert-butyl4-(hydroxymethyl)-1H-benzo[d]imidazole-1-carboxylate (184 mg, 0.741mmol) and 2-(tributylphosphoranylidene)acetonitrile (612 μL, 2.334 mmol)were combined in toluene (3.7 mL) and the reaction mixture heated in a 5mL microwave vial in a Biotage initiator microwave at 120° C. for 30min. The vial was returned to the microwave for a further 30 min at 120°C. An additional portion of 2-(tributylphosphoranylidene)acetonitrile(428 μL, 1.630 mmol) was added, and the reaction was returned to themicrowave for 30 min at 120° C. The reaction mixture was poured ontowater (30 mL) and extracted with ethyl acetate (3×15 mL). The combinedorganic portions were washed with brine, dried through a hydrophobicfrit and evaporated in vacuo to yield the crude product. The residue wasloaded in dichloromethane onto a 50 g SNAP silica cartridge and waspurified via Biotage SP4 flash chromatography, eluting from 10-70% (3:1ethyl acetate:ethanol)/cyclohexane. The relevant fractions were combinedand evaporated in vacuo to yield the product—tert-butyl4-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate(91 mg, 0.195 mmol, 26.4% yield) as a brown glass which was used withoutfurther purification in the subsequent reaction.

LCMS (2 min Formic): Rt=1.03 min, [MH]⁺=466.2.

Intermediate 56: tert-Butyl4-((5-(cyclobutylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate

N5-Cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (55mg, 0.221 mmol), tert-butyl4-(hydroxymethyl)-1H-benzo[d]imidazole-1-carboxylate (69 mg, 0.278 mmol)and 2-(tributylphosphoranylidene)acetonitrile (0.182 mL, 0.695 mmol)were combined in toluene (1.5 mL) and the reaction mixture heated in a 5mL microwave vial in a Biotage initiator at 120° C. for 30 min. Thereaction was returned to the microwave at 120° C. for 20 min. Thereaction mixture was poured onto water (20 mL) and extracted with ethylacetate (3×10 mL). The combined organic portions were washed with brine,dried through a hydrophobic frit and evaporated in vacuo to yield thecrude product. The residue was loaded in dichloromethane onto a 25 gSNAP silica cartridge and purified via Biotage SP4 flash chromatography,eluting from 10-50% (3:1 ethyl acetate:ethanol)/cyclohexane. Therelevant fractions were combined and evaporated in vacuo to yield theproduct tert-butyl4-((5-(cyclobutylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate(54 mg, 0.113 mmol, 51.0% yield) as a brown glass, which was usedwithout further purification.

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=480.2.

Intermediate 57: 2,4,6-Trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

1-Benzyl-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (2 g,6.23 mmol), Xantphos (0.360 g, 0.623 mmol), palladium acetate (0.070 g,0.311 mmol) and Et₃N (1.302 mL, 9.34 mmol) were combined in a threenecked flask equipped with a dropping funnel and a condensor with anitrogen bubbler on the top. Toluene (30 mL) was added and the mixturewas heated at 80° C. under nitrogen for 20 min, then a solution of2,4,6-trichlorophenyl formate (2.106 g, 9.34 mmol) in toluene (20 mL)was added dropwise over 30 min and heating continued for 2 h. Thereaction mixture was diluted with EtOAc (50 mL) and washed with water(50 mL) and brine (50 mL), dried and evaporated in vacuo to give anorange oil. This was dissolved in DCM (10 mL) and loaded onto a 50 gsilica column, then eluted with 0-50% EtOAc/cyclohexane and theproduct-containing fractions evaporated in vacuo to give2,4,6-trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(2.52 g, 5.41 mmol, 87% yield) as a beige solid

LCMS (2 min Formic): Rt=1.36 min, [MH]⁺=465, 467.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 9.32 (br. d, J=4.4 Hz, 1H) 9.20 (d,J=2.7 Hz, 1H) 8.58 (d, J=2.7 Hz, 1H) 7.30-7.50 (m, 7H) 5.29 (s, 2H) 3.01(d, J=4.9 Hz, 3H).

Intermediate 58: 5-Bromo-2-methoxynicotinoyl chloride

5-Bromo-2-methoxynicotinic acid (15 g, 64.6 mmol, commercially availablefrom, for example Apollo Scientific) was suspended in DCM (100 mL) andthen oxalyl chloride (16.98 mL, 194 mmol) was added, followed by DMF(5.01 mL, 64.6 mmol) and the mixture was stirred for 18 h at rt. Thesolvent was evaporated in vacuo and the residue was redissolved in DCM(100 mL) and evaporated to dryness to give 5-bromo-2-methoxynicotinoylchloride (16.33 g, 65.2 mmol, 101% yield) which was used in the nextstep immediately.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 8.49 (d, J=2.7 Hz, 1H) 8.44 (d, J=2.4Hz, 1H) 4.06 (s, 3H).

Intermediate 59: 5-Bromo-2-methoxy-N-methylnicotinamide

5-Bromo-2-methoxynicotinoyl chloride (16 g, 63.9 mmol) was dissolved in2-methyltetrahydrofuran (100 mL) and Et₃N (8.90 mL, 63.9 mmol) wasadded, followed by methanamine (31.9 mL, 2M in THF, 63.9 mmol) and themixture was stirred for 3 h at rt, then added to water (200 mL) andextracted with EtOAc (200 mL). The organic layer was washed with brine(200 mL), dried and evaporated in vacuo to give5-bromo-2-methoxy-N-methylnicotinamide (14.8 g, 60.4 mmol, 95% yield) asa pale yellow solid.

LCMS (2 min High pH): Rt=0.83 min, [MH]⁺=245.1, 247.1.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 8.62 (d, J=2.4 Hz, 1H) 8.29 (d, J=2.4Hz, 1H) 7.80 (br. s., 1H) 4.09 (s, 3H) 3.02 (d, J=4.9 Hz, 3H).

Intermediate 60: Butyl 6-methoxy-5-(methylcarbamoyl)nicotinate

(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.479 g, 4.28mmol), triethylamine (18.58 g, 184 mmol), diacetoxypalladium (0.962 g,4.28 mmol) and 5-bromo-2-methoxy-N-methylnicotinamide (15 g, 61.2 mmol)were combined in a 500 mL RBF, then DMF (100 mL) and 1-butanol (28.0 mL,306 mmol) were added and the mixture was purged with carbon monoxide for10 min, then a balloon containing around 1.5 litre of CO was added andthe mixture was heated overnight at 90° C. The mixture was then cooled,diluted with water (500 mL) and extracted with EtOAc (2×500 mL). Theorganics were washed with water (200 mL), dried and evaporated in vacuoand the resulting black oil was purified by chromatography on a 340 gsilica column eluting with 0-100% EtOAc/cyclohexane to give butyl6-methoxy-5-(methylcarbamoyl)nicotinate (11 g, 41.3 mmol, 67.5% yield)as a pale yellow crystalline solid.

LCMS (2 min High pH): Rt=1.04 min, [MH]⁺=267.2.

Intermediate 61: Methyl 6-methoxy-5-(methylcarbamoyl)nicotinate

Carbon monoxide was gently bubbled through a mixture of5-bromo-2-methoxy-N-methylnicotinamide (10.6 g, 43.3 mmol), xantphos(1.502 g, 2.60 mmol), triethylamine (12.06 mL, 87 mmol), palladium(II)acetate (0.486 g, 2.163 mmol) and methanol (17.50 mL, 433 mmol) in DMF(150 mL) until a yellow/green suspension resulted. The suspension washeld under a balloon of carbon monoxide and heated to 60° C. for 5 h.LCMS showed significant SM, so the reaction was left overnight (16 h).The reaction mixture was then allowed to cool to rt. The solution wasdiluted with water (300 mL) and extracted with EtOAc (3×300 mL), and thecombined organics back extracted with brine (3×100 mL). The combinedorganics were then dried (Na₂SO₄) and evaporated in vacuo to a brownsolid. The residue was dissolved in DCM, loaded on to a 340 g Biotagesilica SNAP column and eluted with 20→80% EtOAc/cyclohexane. The productcontaining fractions were evaporated in vacuo to a yellow solid—methyl6-methoxy-5-(methylcarbamoyl)nicotinate (4 g, 17.84 mmol, 41.2% yield)

As the yield was lower than expected, the retained aqueous layer wasanalysed by LCMS and found to contain further product. This wastherefore further extracted with DCM (3×100 mL), the combined organicswere dried (Na₂SO₄) and concentrated in vacuo (for a prolonged period toremove DMF). The aqueous layer was re-analysed by LCMS and found to nolonger contain product. The crude product from the organic phase, ayellow solid was taken up in DCM and added to a SNAP silica cartridge(100 g) and eluted with 20→80% EtOAc/cyclohexane The product containingfractions were evaporated in vacuo to a yellow solid—methyl6-methoxy-5-(methylcarbamoyl)nicotinate (1.9 g, 8.47 mmol, 19.59% yield)

LCMS (2 min Formic): Rt=0.67 min, [MH]+=225.1.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.82 (d, J=2.2 Hz, 1H) 8.55 (d, J=2.4Hz, 1H) 8.30 (br. d, J=3.9 Hz, 1H) 4.05 (s, 3H) 3.87 (s, 3H) 2.82 (d,J=4.6 Hz, 3H).

Intermediate 62: Methyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Sodium iodide (4.88 g, 32.6 mmol) was added to a solution of methyl6-methoxy-5-(methylcarbamoyl)nicotinate (3.65 g, 16.28 mmol) inacetonitrile (100 mL) and this solution was stirred for 10 min undernitrogen. TMS-Cl (10.40 mL, 81 mmol) was added dropwise, and thereaction mixture was stirred at rt for 1 h. The reaction was quenchedwith water (100 mL) and the mixture was extracted five times with a mixof DCM/MeOH and the combined organic phase was dried over a hydrophobicfrit and evaporated under vacuum. The crude material was dissolved inDCM and loaded onto a 100 g SNAP silica cartridge and eluted with 0-100%ethanol in EtOAc. The appropriate fractions were evaporated undervacuum, and the desired product was obtained—methyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.5 g, 7.14mmol, 43.8% yield).

LCMS (2 min Formic): Rt=0.47 min, [MH]+=211.1.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.25 (br. s, 1H) 9.55 (br. d, J=4.4 Hz,1H) 8.63 (d, J=2.7 Hz, 1H) 8.32 (d, J=2.7 Hz, 1H) 3.80 (s, 3H) 2.82 (d,J=4.9 Hz, 3H).

Intermediate 63: Butyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

TMSCl (15.84 mL, 124 mmol) and sodium iodide (18.58 g, 124 mmol) wereadded to a solution of butyl 6-methoxy-5-(methylcarbamoyl)nicotinate (11g, 41.3 mmol) in acetonitrile (200 mL) at rt, and the mixture wasstirred for 1 h, then evaporated in vacuo and the residue partitionedbetween EtOAc (200 mL) and saturated sodium thiosulphate solution (200mL). The organic layer was washed with brine, dried and evaporated invacuo to give butyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (6.5 g, 25.8mmol, 62.4% yield) as a pale yellow solid.

LCMS (2 min High pH): Rt=0.66 min, [MH]⁺=253.2.

Intermediate 64: Methyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Methyl 5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (580mg, 2.76 mmol), 1-(bromomethyl)-3-methoxybenzene (0.580 mL, 4.14 mmol),potassium carbonate (770 mg, 5.57 mmol) and DMF (5 mL) were stirred at90° C. for 1 h. This was washed with LiCl (20 mL), partitioned betweenEtOAc (40 mL) and water (40 mL), the aqueous phase was extracted withEtOAc (2×40 mL), dried over a hydrophobic frit and concentrated to givea colourless oil. This was purified by chromatography on SiO₂ (BiotageSNAP 100 g cartridge, eluting with 0-100% EtOAc/cyclohexane). Theappropriate fractions were concentrated to give methyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(683 mg, 1.861 mmol, 67.4% yield) as a white solid.

LCMS (2 min Formic): Rt=0.91 min, [MH]+=331.0.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.22 (br. d, J=4.6 Hz, 1H) 8.93 (d,J=2.7 Hz, 1H) 8.70 (d, J=2.7 Hz, 1H) 7.27 (t, J=7.9 Hz, 1H) 6.92 (m,J=1.7 Hz, 1H) 6.84-6.90 (m, 2H) 5.30 (s, 2H) 3.84 (s, 3H) 3.73 (s, 3H)2.83 (s, 3H).

Intermediate 65:1-(3-Methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Methyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(670 mg, 2.028 mmol), lithium hydroxide (146 mg, 6.08 mmol), 1,4-dioxane(3 mL) and water (3 mL) were stirred at rt for 30 min. Acetic acid (1mL, 17.47 mmol) was added and the solution was partitioned between EtOAc(20 mL) and water (20 mL), the aqueous phase was extracted with EtOAc(2×20 mL), dried over a hydrophobic frit and concentrated to give1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (641 mg, 1.824 mmol, 90% yield) as a white solid.

LCMS (2 min Formic): Rt=0.81 min, [MH]+=317.0.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.09 (br. s, 1H) 9.26 (br. q, J=4.4,4.4, 4.4 Hz, 1H) 8.84 (d, J=2.7 Hz, 1H) 8.70 (d, J=2.4 Hz, 1H) 7.27 (t,J=7.9 Hz, 1H) 6.91-6.94 (m, 1H) 6.84-6.90 (m, 2H) 5.29 (s, 2H) 3.73 (s,3H) 2.82 (d, J=4.9 Hz, 3H).

Intermediate 66: Butyl5-(methylcarbamoyl)-6-oxo-1-((1-tosyl-1H-indol-4-yl)methyl-1,6-dihydropyridine-3-carboxylate

To a solution of butyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (447 mg,1.772 mmol) in DMF (11.8 mL) was added potassium carbonate (490 mg, 3.54mmol) and 4-(bromomethyl)-1-tosyl-1H-indole (1033 mg, 2.84 mmol). Themixture was stirred at rt for 2 h. The reaction was quenched with water(1.596 mL, 89 mmol) and poured onto water (100 mL) and saturated aqueouslithium chloride (20 mL). The aqueous phase was extracted with ethylacetate (3×30 mL) and the combined organics were washed with brine (10mL), dried through a hydrophobic frit and evaporated in vacuo to yieldthe crude product (1.74 g). The residue was loaded in dichloromethaneonto a 50 g SNAP silica cartridge and purified via Biotage SP4 flashchromatography, eluting from 20-100% ethyl acetate/cyclohexane. Therelevant fractions were combined and evaporated in vacuo to yield thepure product—butyl5-(methylcarbamoyl)-6-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,6-dihydropyridine-3-carboxylate(907 mg, 1.609 mmol, 91% yield) as a white solid.

LCMS (2 min Formic): Rt=1.34 min, [MH]⁺=536.1.

Intermediate 67:1-((1H-Indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

To a solution of butyl5-(methylcarbamoyl)-6-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,6-dihydropyridine-3-carboxylate(821 mg, 1.533 mmol) in methanol (1.703 mL) and THF (3.406 mL) stirredunder nitrogen at rt was added solid cesium carbonate (3995 mg, 12.26mmol) in one charge. The reaction mixture was stirred at 70° C. for 3 h.The reaction mixture was concentrated in vacuo, before diluting with1,4-dioxane (1.703 mL) and water (1.703 mL). The mixture was stirred at70° C. for 4.5 h. The reaction mixture was poured onto saturated sodiumbicarbonate (30 mL) and extracted with ethyl acetate (3×10 mL). Theaqueous phase was acidified with 2M HCl and extracted with ethyl acetate(8×30 mL). Following extraction, a solid precipitate remained in theorganic phase which was filtered off to give some desired crude product(251 mg). The filtrate from workup was dried through a hydrophobic fritand evaporated in vacuo to yield a brown solid. The solid was trituratedwith ether (30 mL) and filtered to give further product (539 mg). Thisresidue was suspended in water (20 mL) and brought to pH 4 with 2M HCl.The suspension was filtered, washed with water (2×5 mL) and diethylether (2×10 mL). The collected solid (213 mg) was suspended indichloromethane (10 mL) and combined with the previous batch of crudeproduct. The combined suspension was sonicated and blown down under astream of nitrogen and dried in vacuo to give the final product1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (432 mg, 1.222 mmol, 80% yield).

LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=326.2.

Intermediate 68: Butyl 1-(2-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

A stirred suspension of butyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (695.9 mg,2.76 mmol) and potassium carbonate (769.4 mg, 5.57 mmol) in DMF (4 mL)at rt had a solution of 1-(bromomethyl)-2-fluoro-3-methylbenzene (607.4mg, 2.99 mmol) in DMF (6 mL) added to it. The mixture was stirred at rtunder nitrogen for 73 h before being partitioned between water (20 mL)and ethyl acetate (25 mL). The organic phase was washed with furtherwater (20 mL) and the combined aqueous phases back-extracted with ethylacetate (25 mL). The combined organic phases were dried by filteringthrough a cartridge fitted with a hydrophobic frit and the solvent wasevaporated in vacuo to give a pale yellow oil which crystallised uponstanding overnight to a pale yellow solid. The solid was purified bybeing re-dissolved in dichloromethane (ca. 5 mL) and applied to a 50 gSNAP silica cartridge which was eluted with a gradient of 20-60% ethylacetate in cyclohexane. The required fractions were combined andevaporated in vacuo to give the desired product as a white solid (958.7mg).

LCMS (2 min Formic): Rt=1.26 min, [MH]⁺=375.2.

Intermediate 69:1-(2-Fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

To a stirred solution of butyl1-(2-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(953.7 mg, 2.55 mmol) in acetonitrile (10 mL) and THF (10 mL) undernitrogen was added lithium hydroxide (1.0 M aqueous solution) (5.1 mL,5.10 mmol) and the mixture was stirred at rt for 2.5 h. The volatileswere evaporated from the mixture in vacuo and the residue dried in vacuobefore being partitioned between 2 M aqueous hydrochloric acid (20 mL)and ethyl acetate (150 mL) [solid was poorly soluble in both phases].The aqueous phase was extracted with further ethyl acetate (75 mL) andthe combined organic phases washed with water (20 mL) and saturatedbrine solution (30 mL). The organic phase was dried by filtering througha cartridge fitted with a hydrophobic frit and the solvent evaporated invacuo. The solid residue was triturated twice with methanol (10 mL+5 mL)and the solid dried in vacuo to give the desired product as a whitesolid (621.7 mg).

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=319.1.

Intermediate 70: Methyl1-(3-hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Methyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(0.990 g, 3.00 mmol) in DCM (5 mL) was cooled to 0° C. under N₂ and BBr₃(15 mL, 1 M in DCM, 15 mmol) was added dropwise and the reaction stirredfor 1.5 h. The reaction was quenched with water (30 mL), extracted withDCM (2×30 mL), the aqueous layer was then extracted with EtOAc (2×30mL). The combined organic layers were dried over a hydrophobic frit andconcentrated to give 675 mg of a yellow solid. This was purified bychromatography on SiO₂ (Biotage SNAP 50 g cartridge, eluting with40-100% EtOAc/cyclohexane). The appropriate fractions were concentratedto give methyl1-(3-hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(473 mg, 1.346 mmol, 44.9% yield) as a white solid.

LCMS (2 min Formic): Rt=0.74 min, [MH]+=317.0.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.46 (br. s, 1H) 9.23 (br. d, J=4.6 Hz,1H) 8.90 (d, J=2.7 Hz, 1H) 8.70 (d, J=2.7 Hz, 1H) 7.05-7.20 (m, 1H)6.65-6.76 (m, 3H) 5.26 (s, 2H) 3.78-3.90 (m, 3H) 2.82 (d, J=4.9 Hz, 3H).

Intermediate 71: Methyl1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Methyl1-(3-hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(450 mg, 1.423 mmol), 1,3-dioxolan-2-one (475 mg, 5.39 mmol), potassiumcarbonate (600 mg, 4.34 mmol) and DMF (10 mL) were heated at 90° C. for5 h. The solution was partitioned between EtOAc (40 mL) and LiCl soln.(40 mL), the aqueous phase was extracted with EtOAc (2×40 mL), driedover a hydrophobic frit and concentrated to give 900 mg of a yellow oil.This was purified by chromatography on SiO₂ (Biotage SNAP 10 gcartridge, eluting with 0-100% (25% EtOH in EtOAc)/cyclohexane). Theappropriate fractions were concentrated to give methyl1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(446 mg, 1.114 mmol, 78% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.74 min, [MH]+=361.1.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.22 (br. q, J=4.9, 4.9, 4.9 Hz, 1H)8.94 (d, J=2.7 Hz, 1H) 8.70 (d, J=2.4 Hz, 1H) 7.25 (t, J=7.8 Hz, 1H)6.82-6.94 (m, 3H) 5.30 (s, 2H) 4.81 (t, J=5.6 Hz, 1H) 3.95 (t, J=5.0 Hz,2H) 3.84 (s, 3H) 3.69 (q, J=5.3 Hz, 2H) 2.82 (d, J=4.6 Hz, 3H).

Intermediate 72:1-(3-(2-Hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Methyl1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(440 mg, 1.221 mmol), lithium hydroxide (86 mg, 3.59 mmol), 1,4-dioxane(3 mL) and water (3 mL) were stirred at rt for 1 h. Acetic acid (1 mL,17.47 mmol) was added and the solution was partitioned between EtOAc (20mL) and water (20 mL), the aqueous phase was extracted with EtOAc (2×20mL), dried over a hydrophobic frit and concentrated to give1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (343 mg, 0.891 mmol, 73.0% yield) as a white solid.

LCMS (2 min Formic): Rt=0.66 min, [MH]+=347.0.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.27 (br. q, J=4.2, 4.2, 4.2 Hz, 1H)8.85 (d, J=2.4 Hz, 1H) 8.71 (d, J=2.4 Hz, 1H) 7.27 (t, J=7.8 Hz, 1H)6.80-6.99 (m, 3H) 5.30 (s, 2H) 4.82 (t, J=5.5 Hz, 1H) 3.96 (app. t,J=5.0 Hz, 2H) 3.70 (ABq, J=5.1 Hz, 2H) 2.83 (d, J=4.9 Hz, 3H).

Intermediate 73: Methyl1-(3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Methyl 5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(500.2 mg, 2.380 mmol), 1-(bromomethyl)-3-methylbenzene (0.354 mL, 2.62mmol) and potassium carbonate (140 mg, 1.013 mmol) were stirred inanhydrous DMF (10 mL) at rt under nitrogen for 4 h. The reaction mixturewas concentrated in vacuo before being partitioned between water (20 mL)and ethyl acetate (20 mL). The aqueous phase was extracted with furtherethyl acetate (2×20 mL) and the combined organic phases were dried byfiltering through a cartridge fitted with a hydrophobic frit. Thesolvent was evaporated and dried in vacuo to give the desired product,as a pale yellow gum (588.2 mg). The product was used in the subsequentreaction without further purification.

LCMS (2 min Formic): Rt=1.00 min, [MH]+=315.2.

Intermediate 74:1-(3-Methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

A mixture of methyl1-(3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(583.9 mg, 1.858 mmol) and lithium hydroxide (92.4 mg, 3.86 mmol) in THF(10 mL) and water (5.00 mL) was stirred at rt under nitrogen for 16.75h. The mixture was then acidified to pH 0 with a 2M solution ofhydrochloric acid (2 mL). Water (30 mL) was added and the resultingprecipitate extracted with ethyl acetate (20 mL). The layers wereseparated and the aqueous layer further extracted with ethyl acetate(2×20 mL). The organic layers were combined and filtered through acartridge containing a hydrophobic frit before being concentrated invacuo. The residue was applied to a 25 g SNAP silica cartridge as asuspension in ethyl acetate. The precipitate remaining on the top of thecartridge was removed and retained as a portion of the desired product.The cartridge was eluted with a gradient of 0-7.5% ethanol (with 0.3%acetic acid) in ethyl acetate. The required fractions were combined withthe previously obtained solid, evaporated and dried in vacuo to give thedesired product as a white solid (355.4 mg).

LCMS (2 min Formic): Rt=0.88 min, [MH]⁺=301.2.

Intermediate 75: Methyl 1-(2-fluoro-5-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

2-(Bromomethyl)-1-fluoro-4-methylbenzene (412 mg, 2.027 mmol) was addedto a solution of methyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (426 mg,2.027 mmol) and potassium carbonate (560 mg, 4.05 mmol) in DMF (15 mL).The reaction mixture was left to stir at rt for 2 h. The reactionmixture was concentrated under vacuum and partitioned between DCM (20mL) and water (20 mL). The organic layer was concentrated under vacuum,loaded in DCM (3 mL) and purified by Biotage Isolera SNAP 25 g silicachromatography using a gradient of 0-60% cyclohexane/ethyl acetate. Theappropriate fractions were combined and concentrated under vacuum togive the product (310 mg) as a white solid.

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=333.0.

Intermediate 76:1-(2-Fluoro-5-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Methyl1-(2-fluoro-5-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(310 mg, 0.933 mmol) was taken up in THF (4 mL) and water (4 mL).Lithium hydroxide (44.7 mg, 1.866 mmol) was added to the solution andthe reaction stirred overnight at rt. 2M aq. HCl (1.399 mL, 2.80 mmol)was added and resulting solid was washed with water to give the product(290 mg) as a white solid.

LCMS (2 min Formic): Rt=0.89 min, [MH]⁺=319.0.

Intermediate 77:5-Bromo-N-methyl-1-(4-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

To a solution of5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (136 mg, 0.589mmol) in methanol (1 mL) was added potassium carbonate (285 mg, 2.060mmol) and 1-(bromomethyl)-4-methylbenzene (327 mg, 1.766 mmol). Themixture was heated to 65° C. for 3 h. The reaction was quenched withwater (530 μL, 29.4 mmol), and poured onto water (10 mL). The productwas extracted with ethyl acetate (4×10 mL). The combined organics werewashed with brine (10 mL), dried through a hydrophobic frit andevaporated in vacuo to yield the crude product (414 mg). The residue wasloaded in dichloromethane and purified via Biotage SP4 flashchromatography, eluting from 15-75% ethyl acetate/cyclohexane. Therelevant fractions were combined and evaporated in vacuo to yield thepureproduct—5-bromo-N-methyl-1-(4-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(120 mg, 0.358 mmol, 60.8% yield) as a white solid.

LCMS (2 min Formic): Rt=1.04 min, [MH]⁺=335.0, 337.0.

Intermediate 78:5-Bromo-N-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

1-(Bromomethyl)-3-methylbenzene (0.263 mL, 1.948 mmol) was added to asuspension of 5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(300 mg, 1.298 mmol) and potassium carbonate (359 mg, 2.60 mmol) inmethanol (4 mL). The reaction mixture was heated to 65° C. for 2 h,after which further 1-(bromomethyl)-3-methylbenzene (0.263 mL, 1.948mmol) and potassium carbonate (359 mg, 2.60 mmol) were added and thereaction mixture was heated to 65° C. for a further 1 h. The reactionmixture was partitioned between ethyl acetate (20 mL) and water (20 mL)and the organic layer washed with water (2×20 mL). This was passedthrough a hydrophobic frit and the solvent removed under reducedpressure. The resulting yellow oil was dissolved in DCM and purified byflash chromatography on a 25 g Biotage SNAP silica column using agradient of 0-70% cyclohexane/ethyl acetate. The product-containingfractions were combined and the solvent removed under reduced pressure.The product was left to dry in vacuo overnight to give5-bromo-N-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(205.8 mg, 0.614 mmol, 47.3% yield) as a white solid.

LCMS (2 min Formic): Rt=1.05 min, [MH]⁺=335.0 & 337.0.

Intermediate 79:5-Bromo-N-methyl-2-oxo-1-((1-tosyl-1H-indol-7-yl)methyl)-1,2-dihydropyridine-3-carboxamide

To a solution of5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (300 mg, 1.298mmol) in methanol (2.164 mL) was added potassium carbonate (359 mg, 2.60mmol) and 7-(bromomethyl)-1-tosyl-1H-indole (568 mg, 1.558 mmol). Themixture was heated to 65° C. for 5 h in total. The reaction was quenchedwith water (1.170 mL, 64.9 mmol) and taken up in dichloromethane (30mL). The solution was washed with water (20 mL), and the aqueous phasewas back extracted with dichloromethane (2×10 mL). The combined organicportions were dried through a hydrophobic frit and evaporated in vacuoto yield the crude product (700 mg). The residue was loaded indichloromethane onto a 25 g SNAP silica cartridge and purified viaBiotage SP4 flash chromatography, eluting from 15-65% ethylacetate/cyclohexane. The relevant fractions were combined and evaporatedin vacuo to yield an orange oil. The residue was further dried in vacuotoyield—5-bromo-N-methyl-2-oxo-1-((1-tosyl-1H-indol-7-yl)methyl)-1,2-dihydropyridine-3-carboxamide(326 mg, 0.570 mmol, 43.9% yield) as an orange solid.

LCMS (2 min Formic): Rt=1.22 min, [MH]⁺=513.9, 515.9.

Intermediate 80:N5-Cyclopropyl-N3-methyl-2-oxo-1-((1-tosyl-1H-indol-7-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide

To a dry microwave vial,5-bromo-N-methyl-2-oxo-1-((1-tosyl-1H-indol-7-yl)methyl)-1,2-dihydropyridine-3-carboxamide(297 mg, 0.577 mmol) and Pd(OAc)₂ (12.96 mg, 0.058 mmol) were added andtaken up in in dry 1,4-dioxane (3.849 mL). Xantphos (33.4 mg, 0.058mmol), DMAP (141 mg, 1.155 mmol) and cyclopropylamine (81 μL, 1.155mmol) were added followed by dicobalt octacarbonyl (59.2 mg, 0.173mmol). The vial was sealed immediately and heated under microwaveirradiation for 40 min at 80° C. The reaction mixture was filteredthrough celite, concentrated in vacuo, taken up in dichloromethane (30mL) and washed with 2M HCl (30 mL). The acid layer was extracted withdichloromethane (2×10 mL). The combined organic portions were driedthrough a hydrophobic frit and evaporated in vacuo. The crude residue(396 mg) was loaded in dichloromethane onto a 25 g SNAP silica cartridgeand purified via Biotage SP4 flash chromatography, eluting from 10-50%(3:1 ethyl acetate:ethanol)/cyclohexane. The relevant fractions werecombined and evaporated in vacuo toyield—N5-cyclopropyl-N3-methyl-2-oxo-1-((1-tosyl-1H-indol-7-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(251 mg, 0.290 mmol, 50.3% yield) as an orange solid which was usedwithout further purification in subsequent chemistry.

LCMS (2 min Formic): Rt=1.09 min, [MH]⁺=519.0.

Intermediate 81: Methyl1-((1H-indazol-7-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

DIAD (0.185 mL, 0.952 mmol) was added to a suspension of methyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (100 mg,0.476 mmol), (1H-indazol-7-yl)methanol (106 mg, 0.714 mmol, commerciallyavailable from, for example, Fluorochem) and triphenylphosphine (250 mg,0.952 mmol) in toluene (4 mL). The reaction was stirred at rt under N₂for 1.5 h. Further portions of (1H-indazol-7-yl)methanol (106 mg, 0.715mmol), DIAD (0.185 mL, 0.950 mmol) and triphenylphosphine (250 mg, 0.953mmol) were added and reaction mixture continued to stir at rt overnight.The reaction mixture was concentrated to give ˜1.2 g of crude product asan orange oil. This was purified by chromatography on SiO₂ (Biotage SNAP25 g cartridge, eluting with 0-100% ethyl acetate/cyclohexane) to givemethyl1-((1H-indazol-7-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(76 mg, 0.167 mmol, 35.2% yield) as a pale yellow oil.

LCMS (2 min Formic): Rt=0.80 min, [MH]⁺=341.1.

Intermediate 82:1-((1H-Indazol-7-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Methyl1-((1H-indazol-7-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(76 mg, 0.223 mmol) was dissolved in 1,4-dioxane (2 mL). Water (2 mL)was added, followed by LiOH (11 mg, 0.459 mmol) and the reaction mixturestirred at rt for 1.5 h. The dioxane was removed in vacuo and theresidue partitioned between ethyl acetate and sat. NaHCO₃ solution. Theaqueous layer was separated. The aqueous layer was acidified to pH 5with acetic acid (4 mL, 69.9 mmol) and extracted with ethyl acetate(5×30 mL). The combined organic layers were dried (Na₂SO₄) and conc. togive 640 mg of a white solid. This was re-dissolved in water (5 mL) andthe pH adjusted to pH 5 with 2M HCl solution. This was then extractedwith ethyl acetate and the combined organic layers were dried (Na₂SO₄)and conc. to give 544 mg of a white solid. This was dissolved in water(with a small amount of DMSO and MeOH added to solubilise all thematerial) and loaded onto a reverse phase 30 g C18 column. This waseluted with 0-95% MeCN/water with 0.1% formic acid over 10 columnvolumes and the fractions containing the desired product wereconcentrated in vacuo to give1-((1H-indazol-7-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (17 mg, 0.047 mmol, 21% yield) as a white solid.

LCMS (2 min Formic): Rt=0.72 min, [MH]+=327.1.

Intermediate 83:5-Bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

Methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (2 g, 8.62 mmol,commercially available from, for example, CombiBlocks) and 2Mmethylamine in THF (13 mL, 26.0 mmol) were refluxed under N₂. After 4 ha white precipitate had formed. THF (15 mL) was added and the solutionwas refluxed for 1 h. 2M methylamine in THF (13 mL, 26.0 mmol) was addedand the reaction refluxed for 2 h. Further 2M methylamine in THF (22 mL,44.0 mmol) was added and the reaction refluxed overnight. The solutionwas concentrated to give a yellow solid. This was transferred to 2×20 mLmicrowave vials with 2M methylamine in THF (15 mL, 30.0 mmol) and THF(15 mL) and both were heated at 80° C. for 1 h. The suspension from thefirst microwave vial was concentrated, and triturated from diethyl etherto give 5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (880mg). The suspension from the second microwave vial was concentrated andtriturated from diethyl ether to give further5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (880 mg)

LCMS (2 min Formic): Rt=0.50 min, [MH]⁺=231.0, 233.0.

Intermediate 84:5-Bromo-N-methyl-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3-carboxamide

To a solution of5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (300 mg, 1.298mmol) in methanol (2.164 mL) was added potassium carbonate (359 mg, 2.60mmol) and 4-(bromomethyl)-1-tosyl-1H-indole (568 mg, 1.559 mmol). Themixture was heated to 65° C. for 2 h. The reaction was quenched withwater (1.170 mL, 64.9 mmol) and taken up in dichloromethane (30 mL). Thesolution was washed with water (20 mL), and the aqueous phase was backextracted with dichloromethane (2×10 mL). The combined organic portionswere dried through a hydrophobic frit and evaporated in vacuo to yieldthe crude product (607 mg). The residue was loaded in dichloromethaneonto a 25 g SNAP silica cartridge and purified via Biotage SP4 flashchromatography, eluting from 20-100% ethyl acetate/cyclohexane. Therelevant fractions were combined and evaporated in vacuo toyield—5-bromo-N-methyl-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3-carboxamide(312 mg, 0.546 mmol, 42.0% yield) as a white solid.

LCMS (2 min Formic): Rt=1.24 min, [MH]⁺=513.9, 515.9.

Intermediate 85:N5-Cyclopropyl-N3-methyl-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide

To a dry microwave vial,5-bromo-N-methyl-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3-carboxamide(301 mg, 0.585 mmol) and Pd(OAc)₂ (13.14 mg, 0.059 mmol) were added andtaken up in dry 1,4-dioxane (2.5 mL). Xantphos (33.9 mg, 0.059 mmol),DMAP (143 mg, 1.170 mmol) and cyclopropylamine (82 μL, 1.170 mmol) wereadded followed by dicobalt octacarbonyl (60.0 mg, 0.176 mmol). The vialwas sealed immediately and heated under microwave irradiation for 40 minat 80° C. The reaction mixture was filtered through celite, concentratedin vacuo, taken up in dichloromethane (30 mL) and washed with 2M HCl (30mL). The acid layer was extracted with dichloromethane (2×10 mL). Thecombined organic portions were dried through a hydrophobic frit andevaporated in vacuo. The crude residue (361 mg) was loaded indichloromethane onto a 25 g SNAP silica cartridge and purified viaBiotage SP4 flash chromatography, eluting from 10-50% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo to yield a yellowsolid—N5-cyclopropyl-N3-methyl-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(255 mg, 0.320 mmol, 54.6% yield).

LCMS (2 min Formic): Rt=1.10 min, [MH]⁺=519.1.

Intermediate 86:N5-Cyclopropyl-N3-methyl-1-((3-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (80mg, 0.340 mmol) and (3-methyl-1-tosyl-1H-indol-4-yl)methanol (161 mg,0.510 mmol) in toluene (2.267 mL) was added triphenylphosphine (268 mg,1.020 mmol) and DIAD (198 μL, 1.020 mmol). The reaction was stirred atrt under nitrogen. A further portion of(3-methyl-1-tosyl-1H-indol-4-yl)methanol (90 mg, 0.285 mmol) was addedas a suspension in toluene (1 mL). The reaction was stirred for 4 days.Further portions of triphenylphosphine (89 mg, 0.340 mmol) and DIAD (66μL, 0.340 mmol) were added and the reaction stirred for 1.5 h. Thereaction mixture was poured onto water (30 mL). The aqueous phase wasextracted with ethyl acetate (3×15 mL) and the combined organics werewashed with brine (10 mL), dried through a hydrophobic frit andevaporated in vacuo to yield the crude product as a yellow oil (1.376g). The oil was loaded in dichloromethane onto a SNAP cartridge (50 g)and this was purified via Biotage SP4 flash chromatography, eluting from0-50% (3:1 ethyl acetate:ethanol)/cyclohexane. The relevant fractionswere combined and evaporated in vacuo to giveN5-cyclopropyl-N3-methyl-1-((3-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(61 mg, 0.097 mmol, 28.6% yield) as a white solid.

LCMS (2 min Formic): Rt=1.15 min, [MH]⁺=533.3.

Intermediate 87: tert-Butyl4-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)indoline-1-carboxylate

DIAD (0.09 mL, 0.463 mmol) was added to a suspension ofN5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (50mg, 0.213 mmol), tert-butyl 4-(hydroxymethyl)indoline-1-carboxylate (79mg, 0.319 mmol) and triphenylphosphine (117 mg, 0.446 mmol) in toluene(2 mL). The reaction was stirred at rt under N₂ for 2 h. tert-Butyl4-(hydroxymethyl)indoline-1-carboxylate (79 mg, 0.319 mmol), DIAD (0.09mL, 0.463 mmol) and triphenylphosphine (122 mg, 0.465 mmol) were addedand the reaction stirred for 2 h. The reaction was stirred overnight.The reaction was concentrated to give an orange oil (926 mg). This waspurified by chromatography on SiO₂ (Biotage SNAP 100 g cartridge,eluting with 0-100% EtOAc/cyclohexane). The appropriate fractions wereconcentrated to give tert-butyl4-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)indoline-1-carboxylate(41 mg, 0.075 mmol, 35.1% yield) as a colourless oil

LCMS (2 min Formic): Rt=1.08 min, [MH]⁺=467.2.

¹H NMR (400 MHz, MeOH-d₄) δ ppm 8.83 (d, J=2.7 Hz, 1H) 8.47 (d, J=2.7Hz, 1H) 7.60-7.71 (m, 1H) 7.14 (t, J=7.9 Hz, 1H) 6.73 (d, J=7.6 Hz, 1H)5.24 (s, 2H) 4.00 (t, J=8.7 Hz, 2H) 3.14 (t, J=8.7 Hz, 2H) 2.93 (s, 3H)2.80 (tt, J=7.3, 3.7 Hz, 1H) 1.56 (s, 9H) 0.74-0.82 (m, 2H) 0.58-0.65(m, 2H).

Intermediate 88:(+/−)-N5-Cyclopropyl-N3-methyl-2-oxo-1-(1-(1-tosyl-1H-indol-4-yl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide

N5-Cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (53mg, 0.225 mmol), 4-(1-bromoethyl)-1-tosyl-1H-indole (102 mg, 0.270mmol), potassium carbonate (52 mg, 0.376 mmol) and DMF (2 mL) werestirred at 90° C. for 5 h and then overnight. Separately,N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (42mg, 0.179 mmol), 4-(1-bromoethyl)-1-tosyl-1H-indole (102 mg, 0.270mmol), potassium carbonate (45.0 mg, 0.326 mmol) and DMF (1.5 mL) werestirred at 90° C. for 8 h. The resultant suspensions were combined,partitioned between EtOAc (20 mL) and water (20 mL), extracted withEtOAc (20 mL), dried over a hydrophobic frit and concentrated to give anorange oil. This was purified by chromatography on SiO₂ (Biotage SNAP 50g cartridge, eluting with 0-100% EtOAc/cyclohexane). The appropriatefractions were concentrated to give the desired product (66 mg) as ayellow oil. This was purified by MDAP (High pH, injected in 1 mL, 1:1DMSO:MeOH). The appropriate fractions were concentrated to give(+/−)-N5-cyclopropyl-N3-methyl-2-oxo-1-(1-(1-tosyl-1H-indol-4-yl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide(42 mg, 0.071 mmol, 31.5% yield).

LCMS (2 min Formic): Rt=1.15 min, [MH]⁺=533.1.

Intermediate 89: tert-Butyl7-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-2-methyl-1H-benzo[d]imidazole-1-carboxylate

DIAD (0.087 mL, 0.446 mmol) was added to a suspension ofN5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (50mg, 0.213 mmol), tert-butyl4-(hydroxymethyl)-2-methyl-1H-benzo[d]imidazole-1-carboxylate (66.9 mg,0.255 mmol) and triphenylphosphine (117 mg, 0.446 mmol) in toluene (2mL). The reaction was stirred at rt under N₂ overnight. Further DIAD(0.087 mL, 0.446 mmol) and triphenylphosphine (117 mg, 0.446 mmol) wereadded and the reaction stirred for 3 h. The reaction was concentrated,loaded in DCM and purified by chromatography on SiO₂ (Biotage SNAP 10 gcartridge, eluting with 0-100% EtOAc/cyclohexane). The appropriatefractions were concentrated to give the crude product. This was purifiedfurther by MDAP (High pH). The appropriate fractions were combined togive the title compound (14 mg, 0.029 mmol, 13.7% yield)

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=480.2.

Intermediate 90: Butyl5-(methylcarbamoyl)-6-oxo-1-((1,2,3,4-tetrahydroquinolin-8-yl)methyl)-1,6-dihydropyridine-3-carboxylate

DIAD (324 μl, 1.665 mmol) was added to a suspension of butyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (140 mg,0.555 mmol), (1,2,3,4-tetrahydroquinolin-8-yl)methanol (136 mg, 0.832mmol) and triphenylphosphine (437 mg, 1.665 mmol) in toluene (3.7 mL).The reaction was stirred at rt under nitrogen for 1 h. The reactionmixture was poured onto water (30 mL) and the aqueous phase wasextracted with ethyl acetate (3×15 mL). The combined organics werewashed with brine (10 mL), dried through a hydrophobic frit andevaporated in vacuo to yield the crude product as a yellow oil (1.3704g). The oil was loaded in dichloromethane onto a 25 g SNAP silicacartridge and purified via Biotage SP4 flash chromatography eluting from15-75% ethyl acetate/cyclohexane. The relevant fractions were combinedand evaporated in vacuo to yield the purified product—butyl5-(methylcarbamoyl)-6-oxo-1-((1,2,3,4-tetrahydroquinolin-8-yl)methyl)-1,6-dihydropyridine-3-carboxylate(112 mg, 0.248 mmol, 44.7% yield) as a yellow glass.

LCMS (2 min Formic): Rt=1.27 min, [MH]⁺=398.3.

Intermediate 91:5-(Methylcarbamoyl)-6-oxo-1-((1,2,3,4-tetrahydroquinolin-8-yl)methyl)-1,6-dihydropyridine-3-carboxylicacid

Butyl5-(methylcarbamoyl)-6-oxo-1-((1,2,3,4-tetrahydroquinolin-8-yl)methyl)-1,6-dihydropyridine-3-carboxylate(104 mg, 0.262 mmol) was suspended in 1,4-dioxane (534 μL). Water (534μL) was added followed by lithium hydroxide (15 mg, 0.626 mmol) and thereaction mixture stirred at rt for 2.5 h. HCl (2M, 0.313 mL) was addedand the solvents were evaporated in vacuo to yield the required product5-(methylcarbamoyl)-6-oxo-1-((1,2,3,4-tetrahydroquinolin-8-yl)methyl)-1,6-dihydropyridine-3-carboxylicacid (134 mg) as a yellow glass. However the sample contained LiCl fromwork up. Purity estimated at 66%, based on weight, assuming quantitativeyield.

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=342.1.

Intermediate 92: 6-Methoxy-5-(methylcarbamoyl)nicotinic acid

Methyl 6-methoxy-5-(methylcarbamoyl)nicotinate (1.9 g, 8.47 mmol) wastaken up in THF (16 mL) and water (16 mL). Lithium hydroxide (0.223 g,9.32 mmol) was added and the reaction stirred for 16 h at rt. 2M HCl(aq)(4.66 mL, 9.32 mmol) was added and a white precipitate formed, this wasfiltered and washed with further THF/water (40 mL, 1:1). Both theresidue and the filtrate were analysed by LCMS and found to containproduct, therefore these were recombined (washing with MeOH) andconcentrated in vacuo to afford the desired product as a whitesolid—6-methoxy-5-(methylcarbamoyl)nicotinic acid (2.84 g). The sampleis assumed ˜60% purity with the remaining mass due to inorganic impurity(LiCl). This material was used crude in the subsequent reactions.

LCMS (2 min Formic): Rt=0.54 min, [MH]⁺=211.1.

Intermediate 93:2-Methoxy-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)pyridine-3,5-dicarboxamideAND Intermediate 94:2-Methoxy-N3-methyl-N5-((1R,2R)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide

A solution of 6-methoxy-5-(methylcarbamoyl)nicotinic acid (710 mg, 2.027mmol), HATU (1002 mg, 2.63 mmol) and DIPEA (0.708 mL, 4.05 mmol) in DMF(6 mL) was stirred for 5 min before(+/−)-(trans)-2-methylcyclopropanamine (159 mg, 2.229 mmol) was added.The reaction was stirred for 1 h at rt. The reaction was diluted withEtOAc (30 mL) and water (30 mL) then added and the layers separated. Theaqueous layer was further extracted with EtOAc (4×20 mL) and the aqueouslayer analysed and found to have only a small amount of product. Thecombined organics were back-extracted with water (2×10 mL) and brine (10mL) and the organic phase then dried (Na₂SO₄) and concentrated in vacuoto afford the crude product. This was taken up in DCM and added to aSNAP silica cartridge (25 g) and purified by SP4 flash chromatography,eluting with 0-60% (25% EtOH/EtOAc)/cyclohexane. The appropriatefractions were collected and concentrated in vacuo to afford the crudeproduct as a yellowoil—(+/−)-2-methoxy-N3-methyl-N5-((trans)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide(695 mg, 1.980 mmol, 98% yield). The bulk solid was submitted for chiralseparation

Analytical Method:

Column: Chiralpak AD-H (250×4.6 mm)

Flow Rate: 1 mL/min

Detection: UV Diode Array at 280 nm (Band width 140 nm, reference 400 nmbandwidth 100 nm)

Mobile Phase A: Heptane

Mobile Phase B: Propan-2-ol

Isocratic method—90:10 Mobile phase A:Mobile phase B

Runtime—30 min

Preparative Method:

Sample preparation—Total sample dissolved in 30 mL ethanol withsonication.

Column: Chiralpak AD-H (250×30 mm, 5 micron)

Flow Rate: 42.5 mL/min (pressure 85 bar)

Detection: UV Diode Array at 280 nm (Band width 140 nm, reference 400 nmbandwidth 100 nm)

Mobile Phase A: Heptane

Mobile Phase B: Propan-2-ol

Isocratic method—90:10 mobile phase A:mobile phase B

Runtime—30 min

0.3 mL manual injections via Rheodyne valve.

Fractions containing the first eluting isomer were collected in a 1 LDuran bottle between 12 min and 13 min. Fractions containing the secondeluting isomer were collected in a 1 L Duran bottle between 14 min and16 min. The isomer fractions were evaporated to dryness (Rotavapor, 30°C. bath temperature) and then taken up in ethanol (3×4 mL) andtransferred to a tared 20 mL glass vial. A 50 μL sample was taken forfinal chiral hplc analysis and the bulk sample blown down to dynessunder a stream of nitrogen gas. Final chiral HPLC analysis showed thefirst eluting isomer to be 99.3% chirally pure byUV—2-methoxy-N3-methyl-N5-((1R,2R)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide(190 mg, 0.722 mmol, 35.6% yield).

LCMS (2 min Formic): Rt=0.66 min, [MH]⁺=264.1.

Chiral HPLC analysis of the second eluting isomer showed the presence of3.1% (by UV) of the first eluting isomer, a shoulder was evident on themajor isomer peak thus the exact proportion of the first eluting isomerin the sample could not be accuratelyassessed—2-methoxy-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide(216 mg, 0.820 mmol, 40.5% yield)

LCMS (2 min Formic): Rt=0.66 min, [MH]⁺=264.1.

Intermediate 95:N3-Methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Sodium iodide (166 mg, 1.109 mmol) was added to a solution of2-methoxy-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide(146 mg, 0.555 mmol) and TMS-Cl (0.354 mL, 2.77 mmol) in acetonitrile (3mL) and the reaction mixture was stirred at rt for 1 h. The reactionmixture was concentrated in vacuo and taken up in DCM (as a suspension)and added to a SNAP silica (25 g) cartridge which was eluted with 0-50%(20% MeOH/DCM)/DCM. The desired fractions were combined and concentratedin vacuo to afford the desired product as a brownsolid—N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(187 mg, 0.548 mmol, 99% yield)

LCMS (2 min Formic): Rt=0.54 min, [MH]⁺=250.1.

Intermediate 96:N3-Methyl-N5-((1R,2R)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Sodium iodide (56.9 mg, 0.380 mmol) was added to a solution of2-methoxy-N3-methyl-N5-((1R,2R)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide(50 mg, 0.190 mmol) and TMS-Cl (0.121 mL, 0.950 mmol) in acetonitrile (1mL) and the reaction mixture was stirred at rt for 1 h. The reactionmixture was concentrated in vacuo and taken up in DCM (as a suspension)and added to a SNAP silica 10 g cartridge which was eluted with 0-50%(20% MeOH/DCM)/DCM. The desired fractions were combined and concentratedin vacuo to afford the desired product as a yellowsolid—N3-methyl-N5-((1R,2R)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(60 mg). Due to the additional mass, the product is assumed to becontaminated with inorganic impurities, assume 79% purity.

LCMS (2 min Formic): Rt=0.54 min, [MH]⁺=250.1.

Intermediate 97:5-Bromo-1-(3-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

To a solution of5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (150 mg, 0.649mmol) in methanol (1 mL) was added potassium carbonate (179 mg, 1.298mmol) and 1-(bromomethyl)-3-fluorobenzene (116 μL, 0.946 mmol). Themixture was heated to 65° C. for 6 h. A further portion of potassiumcarbonate (90 mg, 0.649 mmol) and 1-(bromomethyl)-3-fluorobenzene (119μL, 0.974 mmol) were added, and the stirring was continued for a further2.7 h. The reaction was quenched with water (585 μL, 32.5 mmol),concentrated in vacuo and poured onto water (15 mL). The product wasextracted with ethyl acetate (10 mL) and dichloromethane (3×10 mL, dueto insolubility in ethyl acetate). The ethyl acetate layer was washedwith brine (10 mL), dried through a hydrophobic frit and evaporated invacuo. To the residue was added the (frit dried) DCM portions, beforeevaporating again in vacuo to yield the crude product (286 mg). Theresidue was dry loaded in dichloromethane onto a 25 g SNAP silicacartridge and purified via Biotage SP4 flash chromatography, elutingfrom 15-75% ethyl acetate/cyclohexane. The relevant fractions werecombined and evaporated in vacuo to yield the pureproduct—5-bromo-1-(3-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(135 mg, 0.398 mmol, 61.3% yield) as a white solid.

LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=338.9, 340.9.

Intermediate 98:5-Bromo-1-((6-methoxypyridin-3-yl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

5-(Bromomethyl)-2-methoxypyridine (144 mg, 0.714 mmol) was added to asolution of 5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(165 mg, 0.714 mmol) and potassium carbonate (197 mg, 1.428 mmol), inDMF (5 mL). The reaction mixture was left to stir at rt overnight. Thereaction mixture was concentrated under vacuum and partitioned betweenDCM (20 mL) and water (20 mL). The organic solution was concentratedunder vacuum, loaded in DCM (3 mL) and purified by Biotage Isolera SNAP25 g silica flash chromatography using a gradient of 0-100%cyclohexane/ethyl acetate. The appropriate fractions were combined andconcentrated under vacuum to give the product (152 mg) as a white solid.

LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=352.0 & 353.9.

Intermediate 99: Methyl1-(3-acetylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

To a solution of methyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (350 mg,1.665 mmol) in DMF (8.326 mL) was added potassium carbonate (460 mg,3.33 mmol) and 1-(3-(chloromethyl)phenyl)ethanone (371 μL, 2.498 mmol).The mixture was stirred at rt for 1.3 h. A further portion of1-(3-(chloromethyl)phenyl)ethanone (124 μL, 0.833 mmol) was added andthe reaction stirring was continued for 3.75 h. The reaction was pouredonto saturated aqueous lithium chloride (100 mL). The aqueous phase wasextracted with ethyl acetate (4×20 mL). The combined organics werewashed with brine (10 mL), dried through a hydrophobic frit andevaporated in vacuo to yield the crude product as an orange gum. Theresidue was loaded in dichloromethane onto a 25 g SNAP silica cartridgeand purified via Biotage SP4 flash chromatography, eluting from 15-75%(3:1 ethyl acetate:ethanol)/cyclohexane. The relevant fractions werecombined and evaporated in vacuo to yield the product (431 mg) as acolourless gum. This was dissolved in ethyl acetate (60 mL) and washedwith water (2×20 mL) and brine (20 mL). The aqueous layer was backextracted with diethyl ether (2×20 mL). The combined organic layers weredried through a hydrophobic frit and evaporated in vacuo to yield—methyl1-(3-acetylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(420 mg, 1.165 mmol, 70.0% yield) as a white solid.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=343.1.

Intermediate 100:1-(3-Acetylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Methyl1-(3-acetylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(355 mg, 1.037 mmol) was suspended in 1,4-dioxane (3.116 mL). Water(2.116 mL) was added followed by lithium hydroxide (62.1 mg, 2.59 mmol)and the reaction mixture stirred at rt for 1 h. HCl (2M, 1.295 mL) wasadded and the solvents were evaporated in vacuo to yield the requiredproduct—1-(3-acetylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (503 mg) as a white solid. However the sample contained LiCl fromwork up. Purity estimated at 67%, based on weight, assuming quantitativeyield.

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=329.1.

Intermediate 101: rac-Butyl5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate

Butyl 5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (158mg, 0.626 mmol), 1-(1-bromoethyl)-3-methylbenzene (197 mg, 0.990 mmol),potassium carbonate (172 mg, 1.245 mmol) and DMF (1.4 mL) were stirredat 90° C. for 1 h. LiCl solution (20 mL) was added and reaction mixturewas partitioned between EtOAc (40 mL) and water (40 mL). The aqueousphase was extracted with EtOAc (2×40 mL) and the combined organic layerswere dried over a hydrophobic frit and concentrated to give 299 mg of ayellow oil. This was purified by chromatography on SiO₂ (Biotage SNAP 25g cartridge, eluting with 0-50% EtOAc/cyclohexane). The appropriatefractions were concentrated to give rac-butyl5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate(193 mg, 0.469 mmol, 74.9% yield) as a white solid.

LCMS (2 min Formic): Rt=1.28 min, [MH]+=371.

Intermediate 102:rac-5-(Methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylicacid

Butyl5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate(200 mg, 0.540 mmol), lithium hydroxide (39 mg, 1.629 mmol), 1,4-dioxane(2 mL) and water (2 mL) were stirred at rt for 1 h. Acetic acid (1 mL,17.47 mmol) was added and the solution was partitioned between EtOAc (20mL) and water (20 mL), the aqueous phase was extracted with EtOAc (2×20mL), dried over a hydrophobic frit and concentrated to giverac-5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylicacid (188 mg, 0.538 mmol, 100% yield) as a white solid.

LCMS (2 min Formic): Rt=0.94 min, [MH]+=315.

Intermediate 103: rac-Butyl5-(methylcarbamoyl)-6-oxo-1-(1-(o-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate

Butyl 5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (300mg, 1.189 mmol), 1-(1-bromoethyl)-2-methylbenzene (670 mg, 3.37 mmol),potassium carbonate (329 mg, 2.378 mmol) and DMF (4 mL) were stirred at90° C. for 1 h. The reaction mixture was washed with LiCl solution (20mL) and partitioned between EtOAc (20 mL) and water (20 mL). The aqueousphase was extracted with EtOAc (2×20 mL) and the combined organic layerswere dried over a hydrophobic frit and concentrated to give 790 mg of anorange oil. This was purified by chromatography on SiO₂ (Biotage SNAP100 g cartridge, eluting with 0-100% EtOAc/cyclohexane). The appropriatefractions were concentrated to give rac-butyl5-(methylcarbamoyl)-6-oxo-1-(1-(o-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate(410 mg, 0.996 mmol, 84% yield) as a colourless oil.

LCMS (2 min Formic): Rt=1.28 min, [MH]+=371.

Intermediate 104:rac-5-(Methylcarbamoyl)-6-oxo-1-(1-(o-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylicacid

Butyl5-(methylcarbamoyl)-6-oxo-1-(1-(o-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylate(410 mg, 1.107 mmol), lithium hydroxide (82 mg, 3.42 mmol), 1,4-dioxane(3 mL) and water (3 mL) were stirred at rt for 1 h. Acetic acid (1 mL,17.47 mmol) was added and the solution was partitioned between EtOAc (20mL) and water (20 mL), the aqueous phase was extracted with EtOAc (2×20mL) and the combined organic layers were dried over a hydrophobic fritand concentrated to giverac-5-(methylcarbamoyl)-6-oxo-1-(1-(o-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylicacid (438 mg, 1.254 mmol, 113% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.92 min, [MH]+=315.

Intermediate 105: Butyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Butyl 5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (198mg, 0.785 mmol), 1-(bromomethyl)-3-methoxybenzene (0.165 mL, 1.177mmol), potassium carbonate (220 mg, 1.592 mmol) and DMF (2 mL) werestirred at 90° C. for 1 h. The reaction mixture was washed with LiClsolution (20 mL), partitioned between EtOAc (40 mL) and water (40 mL)and the aqueous phase was extracted with EtOAc (2×40 mL). The combinedorganic layers were dried over a hydrophobic frit and concentrated togive 680 mg of an orange oil. This was purified by chromatography onSiO₂ (Biotage SNAP 100 g cartridge, eluting with 0-80%EtOAc/cyclohexane). The appropriate fractions were concentrated to givebutyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(266 mg, 0.643 mmol, 82% yield) as a white solid.

LCMS (2 min Formic): Rt=1.15 min, [MH]+=373.

Intermediate 106:1-(3-Hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Butyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(135 mg, 0.362 mmol) in DCM (0.6 mL) was cooled to 0° C. under N₂ andBBr₃ (1.8 mL, 1M in DCM, 1.800 mmol) was added dropwise. After 2 h thereaction was warmed to rt and more BBr₃ (1.8 mL, 1M in DCM, 1.800 mmol)was added. After stirring for a further 2 h, the reaction was quenchedwith methanol (20 mL) and concentrated. This was repeated three times togive crude1-(3-hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (157 mg, 0.390 mmol, 107% yield) as an orange solid.

LCMS (2 min Formic): Rt=0.66 min, [MH]+=303.

Intermediate 107:N5-Cyclopropyl-1-(3-hydroxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(3-Hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (158 mg, 0.392 mmol), HATU (222 mg, 0.584 mmol), DIPEA (0.28 mL,1.603 mmol), cyclopropanamine (0.054 mL, 0.784 mmol) and DMF (2 mL) werestirred at rt under N₂ for 1 h. LiCl solution (20 mL) was added and thereaction mixture was partitioned between EtOAc (20 mL) and water (20mL), the aqueous phase was extracted with EtOAc (2×20 mL) and thecombined organic layers dried over a hydrophobic frit and concentratedto give 476 mg of a yellow oil. This was purified by chromatography onSiO₂ (Biotage SNAP 50 g cartridge, eluting with 0-100% (25% EtOH inEtOAc)/cyclohexane). The appropriate fractions were concentrated to give147 mg of a white solid. This was further purified by MDAP (Formic). Theappropriate fractions were concentrated to giveN5-cyclopropyl-1-(3-hydroxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(46 mg, 0.121 mmol, 30.9% yield) as the desired product.

LCMS (2 min Formic): Rt=0.69 min, [MH]+=342.

Intermediate 108:5-Bromo-1-(3-chlorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

1-(Bromomethyl)-3-chlorobenzene (0.097 mL, 0.736 mmol) was added to asuspension of 5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(170 mg, 0.736 mmol) and potassium carbonate (203 mg, 1.472 mmol) in DMF(5 mL). The reaction mixture was left to stir at rt for 2 h. Thereaction mixture was concentrated under vacuum and partitioned betweenDCM (20 mL) and water (20 mL). The organic layer was concentrated undervacuum, loaded in DCM (3 mL) and purified by Biotage Isolera SNAP 25 gsilica flash chromatography using a gradient of 0-60% cyclohexane/ethylacetate. The appropriate fractions were combined and concentrated undervacuum to give the product (220 mg) as a white solid.

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=354.9 & 356.9.

Intermediate 109:5-Bromo-1-(4-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

To a solution of5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (150 mg, 0.649mmol) in methanol (3 mL) was added potassium carbonate (179 mg, 1.298mmol) and 1-(bromomethyl)-4-fluorobenzene (118 μL, 0.947 mmol). Themixture was heated to 65° C. for 10.5 h. Heating was suspended over theweekend. Following this, a further portion of1-(bromomethyl)-4-fluorobenzene (81 μL, 0.649 mmol) and potassiumcarbonate (90 mg, 0.649 mmol) were added and heating was continued for afurther 5 h. A further portion of 1-(bromomethyl)-4-fluorobenzene (81μL, 0.649 mmol) was added and the reaction was continued for 2.5 h. Thereaction was quenched with water (585 μL, 32.5 mmol), concentrated invacuo and poured onto water (20 mL). The product was extracted withethyl acetate (4×10 mL). The combined organics were washed with brine,dried through a hydrophobic frit and evaporated in vacuo to yield thecrude product (336 mg). The residue was loaded in dichloromethane andpurified via Biotage SP4 flash chromatography, eluting from 15-75% ethylacetate/cyclohexane. The relevant fractions were combined and evaporatedin vacuo to yield the pureproduct—5-bromo-1-(4-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(127 mg, 0.374 mmol, 57.7% yield) as a white solid.

LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=339.0, 341.0.

Intermediate 110:5-Bromo-1-(3-(bromomethyl)benzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

5-Bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (118 mg, 0.511mmol), 1,3-bis(bromomethyl)benzene (162 mg, 0.613 mmol) and potassiumcarbonate (106 mg, 0.766 mmol) were suspended in acetonitrile (2 mL) andthe reaction mixture stirred at 65° C. under N₂ for 2 h. The reactionwas heated further at 80° C. overnight. The reaction mixture was usedcrude in subsequent reactions with no further purification.

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=415.0.

Intermediate 111:5-Bromo-N-methyl-1-(3-(morpholinomethyl)benzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

A crude solution of5-bromo-1-(3-(bromomethyl)benzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(118 mg, 0.285 mmol) (assumed input mass from estimated purity ofpreceding step, containing unreacted SM and other impurities) inacetonitrile (2 mL) and morpholine (124 mg, 1.425 mmol) was added. Thereaction mixture was heated at 70° C. under N₂. The reaction mixture wasconcentrated and suspended in MeOH. This was loaded onto a 2 g SCXcartridge (pre-eluted with MeOH) and eluted with MeOH (40 mL) followedby 2M NH₃ in MeOH (40 mL). All fractions were combined and concentratedto give 318 mg of crude pale yellow solid. This was purified bychromatography on SiO₂ (Biotage SNAP 25 g cartridge, eluting with 0-100%(25% ethanol/ethyl acetate)/cyclohexane over 330 mL). The fractionscontaining the desired product were combined and concentrated in vacuoto give5-bromo-N-methyl-1-(3-(morpholinomethyl)benzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(79 mg, 0.188 mmol, 66.0% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.45 min, [MH]⁺=420, 422.

Intermediate 112:5-Bromo-N-methyl-2-oxo-1-(quinoxalin-5-ylmethyl)-1,2-dihydropyridine-3-carboxamide

5-Bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (213 mg, 0.922mmol), 5-(bromomethyl)quinoxaline (308 mg, 1.383 mmol), potassiumcarbonate (254 mg, 1.838 mmol) and methanol (2 mL) were stirred at 65°C. for 1 h. The resulting solution was concentrated to give 815 mg of anorange solid. This was partitioned between EtOAc (10 mL) and water (10mL). The aqueous phase was extracted with EtOAc (2×20 mL), dried over ahydrophobic frit and concentrated to give 400 mg of a brown oil. Thiswas purified by chromatography on SiO₂ (Biotage SNAP 50 g cartridge,eluting with 0-100% ethyl acetate/cyclohexane). The appropriatefractions were concentrated to give5-bromo-N-methyl-2-oxo-1-(quinoxalin-5-ylmethyl)-1,2-dihydropyridine-3-carboxamide(127 mg, 0.306 mmol, 33.2% yield) as an orange solid.

LCMS (2 min Formic): Rt=0.87 min, [MH]⁺=373, 375.

Intermediate 113:5-Bromo-1-(4-methoxybenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

5-Bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (205 mg, 0.887mmol), 1-(bromomethyl)-4-methoxybenzene (274 mg, 1.363 mmol), potassiumcarbonate (250 mg, 1.809 mmol) and methanol (2 mL) were stirred at 65°C. under N₂ for 1.5 h. A further portion of1-(bromomethyl)-4-methoxybenzene (324 mg, 1.611 mmol) was added andreaction mixture was stirred overnight. The resulting solution wasconcentrated to give an orange solid. This was partitioned between EtOAc(10 mL) and water (10 mL), the aqueous phase was extracted with EtOAc(2×20 mL), dried over a hydrophobic frit and concentrated to give 650 mgof an orange oil. This was purified by chromatography on SiO₂ (BiotageSNAP 50 g cartridge, eluting with 0-100% diethylether/cyclohexane). Theappropriate fractions were concentrated to give5-bromo-1-(4-methoxybenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(85 mg, 0.218 mmol, 24.55% yield) as a white solid

LCMS (2 min Formic): Rt=0.97 min, [MH]⁺=351, 353.

Intermediate 114:1-((1H-Indazol-4-yl)methyl)-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

5-Bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (130 mg, 0.563mmol), 4-(bromomethyl)-1H-indazole, hydrobromide (214 mg, 0.731 mmol),potassium carbonate (223 mg, 1.614 mmol) and DMF (4 mL) were stirred at90° C. for 2 h. LiCl solution (20 mL) was added and reaction mixture waspartitioned between EtOAc (20 mL) and water (20 mL). The aqueous phasewas extracted with EtOAc (2×20 mL), dried over a hydrophobic frit andconcentrated to give 430 mg of an orange oil. This was purified bychromatography on SiO₂ (Biotage SNAP 50 g cartridge, eluting with 0-100%(25% EtOH in EtOAc)/cyclohexane). The appropriate fractions wereconcentrated to give1-((1H-indazol-4-yl)methyl)-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(234 mg, 0.453 mmol, 81% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.78 min, [MH]⁺=361, 363.

Intermediate 115:1-((1H-Indazol-7-yl)methyl)-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

5-Bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (312 mg, 1.350mmol), 7-(bromomethyl)-1H-indazole, hydrobromide (415 mg, 1.421 mmol),potassium carbonate (558 mg, 4.04 mmol) and DMF (5 mL) were stirred at90° C. for 1 h. LiCl solution (20 mL) was added and the reaction mixturewas partitioned between EtOAc (20 mL) and water (20 mL), the aqueousphase was extracted with EtOAc (2×20 mL), dried over a hydrophobic fritand concentrated to give a cream solid. This was purified bychromatography on SiO₂ (Biotage SNAP 50 g cartridge, eluting with 0-60%(25% EtOH in EtOAc)/cyclohexane). The appropriate fractions wereconcentrated to give1-((1H-indazol-7-yl)methyl)-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(396 mg, 0.877 mmol, 65.0% yield) as an off white solid.

LCMS (2 min Formic): Rt=0.86 min, [MH]⁺=361, 363.

Intermediate 116:1-Benzyl-5-bromo-N-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide

1-Benzyl-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (1.09 g,3.54 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (0.929 mL,10.61 mmol) and DMF (0.014 mL, 0.177 mmol) were added, then the mixturestirred at rt for 1 h. The solution was concentrated under vacuum anddissolved in THF (10 mL), cyclopropanamine (0.735 mL, 10.61 mmol) wasadded to the solution. The mixture was stirred for 2 h, then evaporatedin vacuo and the residue partitioned between DCM (50 mL) and saturatedsodium bicarbonate solution. The organic layer was washed with brine,dried and evaporated in vacuo to give the product (1.07 g) as an orangesolid.

LCMS (2 min Formic): Rt=1.07 min, MH+=346.9 & 348.9.

Intermediate 117:5-Bromo-1-(4-fluoro-3-methylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

5-Bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (195 mg, 0.844mmol), potassium carbonate (233 mg, 1.688 mmol) in a solution of DMF (5mL) were stirred at rt and 4-(bromomethyl)-1-fluoro-2-methylbenzene (257mg, 1.266 mmol) was added dropwise. The reaction mixture was allowed tostir at rt for 3 h. The reaction mixture was concentrated under vacuum,redissolved in ethyl acetate (30 mL) and washed with water (30 mL). Thesolution was concentrated under vacuum, loaded in DCM and purified byBiotage Isolera SNAP 25 g silica flash chromatography using a gradientof 0-55% cyclohexane/ethyl acetate. The appropriate fractions werecombined and concentrated under vacuum to give the product (188 mg).

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=353.0 & 355.0.

Intermediate 118:5-Bromo-1-(2-fluoro-3-methylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

1-(Bromomethyl)-2-fluoro-3-methylbenzene (176 mg, 0.866 mmol) was addedto a suspension of5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (200 mg, 0.866mmol) and potassium carbonate (239 mg, 1.731 mmol), in DMF (5 mL). Thereaction mixture was left to stir at rt for 2 h. The reaction mixturewas concentrated under vacuum and partitioned between DCM (20 mL) andwater (20 mL). The organic solution was concentrated under vacuum,loaded in DCM (3 mL) and purified by Biotage Isolera SNAP 25 g silicaflash chromatography using a gradient of 0-60% cyclohexane/ethylacetate. The appropriate fractions were combined and concentrated undervacuum to give the product (200 mg).

LCMS (2 min Formic): Rt=1.08 min, MH+=353.0 & 354.9.

Intermediate 119:5-Bromo-1-(3,5-dimethylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

1-(Bromomethyl)-3,5-dimethylbenzene (155 mg, 0.779 mmol) was added to asolution of 5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(180 mg, 0.779 mmol) and potassium carbonate (215 mg, 1.558 mmol), inDMF (5 mL). The reaction mixture was left to stir at rt for 2 h. Thereaction mixture was concentrated under vacuum and partitioned betweenDCM (20 mL) and water (20 mL). The organic solution was concentratedunder vacuum, loaded in DCM (3 mL) and purified by Biotage Isolera SNAP25 g silica flash chromatography using a gradient of 0-60%cyclohexane/ethyl acetate. The appropriate fractions were combined andconcentrated under vacuum to give the product (160 mg) as a solid.

LCMS (2 min formic): Rt=1.14 min, [MH]⁺=349.0 & 351.0.

Intermediate 120:5-Bromo-1-(2-fluoro-5-methylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

2-(Bromomethyl)-1-fluoro-4-methylbenzene (0.264 mL, 1.948 mmol) wasadded to a suspension of5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (300 mg, 1.298mmol) and potassium carbonate (359 mg, 2.60 mmol) in DMF (5 mL). Thereaction mixture was stirred under nitrogen for 1 h. The reactionmixture was partitioned between ethyl acetate and water and the organiclayer washed with 2× water. The organic layer was passed through ahydrophobic frit and the solvent removed under reduced pressure. Theyellow oil was dissolved in DCM and loaded onto a 25 g Biotage SNAPcolumn which was eluted in cyclohexane:ethyl acetate (0-75%). Theproduct containing fractions were combined and the solvent removed underreduced pressure to give the product (330 mg) as a pale yellow solid.

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=352.9 & 354.9

Intermediate 121:5-Bromo-N-methyl-2-oxo-1-(quinolin-8-ylmethyl)-1,2-dihydropyridine-3-carboxamide

8-(Bromomethyl)quinoline (288 mg, 1.298 mmol) was added to a solution of5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (200 mg, 0.866mmol) and potassium carbonate (239 mg, 1.731 mmol), in DMF (5 mL). Thereaction mixture was left to stir at rt overnight. The reaction mixturewas concentrated under vacuum and partitioned between DCM (20 mL) andwater (20 mL). The organic layer was concentrated under vacuum, loadedin DCM (3 mL) and purified by Biotage Isolera SNAP 25 g silica flashchromatography using a gradient of 0-80% cyclohexane/ethyl acetate. Theappropriate fractions were combined and concentrated under vacuum togive the product (220 mg).

LCMS (2 min Formic): Rt=1.01 min, [MH]⁺=372.1 & 374.1.

Intermediate 122: tert-Butyl5-((5-(methoxycarbonyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

DIAD (0.11 mL, 0.566 mmol) was added to a suspension of methyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (60 mg,0.285 mmol), tert-butyl5-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (110 mg,0.418 mmol) and triphenylphosphine (152 mg, 0.580 mmol) in toluene (2mL). The reaction was stirred at rt under N₂ for 1 h. Further portionsof DIAD (0.11 mL, 0.566 mmol) and triphenylphosphine (150 mg, 0.571mmol) were added and the reaction mixture stirred for a further 1 h.Further portions of DIAD (0.11 mL, 0.566 mmol) and triphenylphosphine(150 mg, 0.571 mmol) were added and reaction mixture was stirred for afurther 1 h. The reaction was partitioned between EtOAc (20 mL) andwater (20 mL), the aqueous layer was extracted with EtOAc (2×20 mL) andthe combined organic layers were dried over a hydrophobic frit andconcentrated to give 1.3 g of an orange oil. This was purified bychromatography on SiO₂ (Biotage SNAP 100 g cartridge, eluting with0-100% ethyl acetate/cyclohexane). The appropriate fractions wereconcentrated to give tert-butyl5-((5-(methoxycarbonyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(522 mg, 0.236 mmol, 83% yield) as a white solid.

LCMS (2 min Formic): Rt=1.13 min, [MH]+=456.3.

Intermediate 123:1-((2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

tert-Butyl5-((5-(methoxycarbonyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(522 mg, 0.241 mmol), lithium hydroxide (25 mg, 1.044 mmol), 1,4-dioxane(3 mL) and water (3 mL) were stirred at rt for 1 h. The solution wasdiluted with sat. aq. sodium bicarbonate (20 mL) and extracted withEtOAc (2×20 mL), the aqueous layer was then acidified to pH 4 withacetic acid and was then extracted with EtOAc (3×20 mL). The combinedorganic layers were dried over a hydrophobic frit and concentrated togive1-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (71 mg, 0.145 mmol, 60.1% yield) LCMS (2 min Formic): Rt=1.03 min,[MH]+=442.

Intermediate 124: tert-Butyl5-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

1-((2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (67 mg, 0.152 mmol), HATU (88 mg, 0.231 mmol), DIPEA (0.08 mL,0.458 mmol), cyclopropanamine (0.03 mL, 0.433 mmol) and DMF (1 mL) werestirred at rt under N₂ for 2 h. Further portions of HATU (92 mg, 0.242mmol), DIPEA (0.08 mL, 0.458 mmol) and cyclopropanamine (0.03 mL, 0.433mmol) were added and the reaction was stirred for a further 3 h at rt.Further portions of HATU (84 mg, 0.221 mmol), DIPEA (0.08 mL, 0.458mmol) and cyclopropanamine (0.03 mL, 0.426 mmol) were added and thereaction mixture stirred for a further 1 h at rt. The reaction mixturewas washed with water (20 mL), partitioned between EtOAc (20 mL) andwater (20 mL), the aqueous phase was extracted with EtOAc (2×20 mL) andthe combined organic layers were dried over a hydrophobic frit andconcentrated to give an orange oil. This was purified by chromatographyon SiO₂ (Biotage SNAP 25 g cartridge, eluting with 0-100%EtOAc/cyclohexane followed by 25% EtOH in EtOAc). The appropriatefractions were concentrated to give 31 mg of a colourless oil. This wasfurther purified by MDAP (Formic). The appropriate fractions wereconcentrated to give tert-butyl5-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(4.2 mg, 7.87 μmol, 5.18% yield) as a colourless oil.

LCMS (2 min Formic): Rt=1.04 min, [MH]+=481.

Intermediate 125: tert-Butyl(6-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)spiro[3.3]heptan-2-yl)carbamate

2,4,6-Trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (80mg, 0.172 mmol), N,N-dimethylpyridin-4-amine (5 mg, 0.041 mmol),tert-butyl (6-aminospiro[3.3]heptan-2-yl)carbamate (78 mg, 0.344 mmol),triethylamine (0.08 mL, 0.574 mmol) and THF (1 mL) were stirred at 45°C. under N₂ for 3 h. The reaction mixture was concentrated to give 200mg of an off white solid which was purified by chromatography on SiO₂(Biotage SNAP 10 g cartridge, eluting with 0-60% (25% EtOH inEtOAc)/cyclohexane). The desired fractions were concentrated to givetert-butyl(6-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)spiro[3.3]heptan-2-yl)carbamate(86 mg, 0.148 mmol, 86% yield) as a colourless oil.

LCMS (2 min Formic): Rt=1.09 min, [MH]⁺=495.

Intermediate 126: tert-Butyl7-((5-bromo-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

DIAD (0.1 mL, 0.514 mmol) was added to a suspension of5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (100 mg, 0.433mmol), tert-butyl7-(hydroxymethyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (180mg, 0.649 mmol) and triphenylphosphine (134 mg, 0.511 mmol) in toluene(3 mL). The reaction was stirred at rt under N₂ for 1 h. Furtherportions of DIAD (0.1 mL, 0.514 mmol) and triphenylphosphine (136 mg,0.519 mmol) were added and the reaction mixture was stirred for afurther 1 h. The reaction mixture was partitioned between EtOAc (20 mL)and water (20 mL), the aqueous layer was extracted with more EtOAc (2×20mL) and the combined organic layers were dried over a hydrophobic fritand concentrated to give 1.06 g of a yellow oil. This was purified bychromatography on SiO₂ (Biotage SNAP 100 g cartridge, eluting with0-100% ethylacetate/cyclohexane). The appropriate fractions wereconcentrated to give tert-butyl7-((5-bromo-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4,5-dihydro-H-benzo[d]azepine-3(2H)-carboxylate(193 mg, 0.354 mmol, 82% yield) as a colourless oil LCMS (2 min Formic):Rt=1.22 min, [MH]⁺=490, 492.

Intermediate 127: tert-Butyl7-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

tert-Butyl7-((5-bromo-3-(methylcarbamoyl)-2-oxopyridin-(2H)-yl)methyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(190 mg, 0.387 mmol), cobalt carbonyl (40 mg, 0.117 mmol),cyclopropanamine (0.054 mL, 0.775 mmol), DMAP (97 mg, 0.794 mmol),palladium acetate (5 mg, 0.022 mmol) and xantphos (13 mg, 0.022 mmol)were combined in a microwave vial and de-gassed, 1,4-Dioxane (3.5 mL)was added and the vial was heated at 80° C. for 40 min. The reactionmixture was filtered through celite and partitioned between water andEtOAc, washed with 2M HCl and extracted with EtOAc (2×30 mL). Theorganic layers were combined and dried over a hydrophobic frit andconcentrated to give 240 mg of a green oil. This was purified bychromatography on SiO₂ (Biotage SNAP 25 g cartridge, eluting with 0-50%(25% EtOH in EtOAc)/cyclohexane). The appropriate fractions wereconcentrated to give 175 mg of a yellow oil. This was further purifiedby MDAP (Formic). The appropriate fractions were concentrated to givetert-butyl7-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(99 mg, 0.160 mmol, 41.3% yield) as a colourless oil.

LCMS (2 min Formic): Rt=1.06 min, [MH]⁺=495.

Intermediate 128: Butyl1-(4-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

4-(Bromomethyl)-1-fluoro-2-methylbenzene (0.805 g, 3.96 mmol) was addedto a solution of butyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1 g, 3.96mmol) and potassium carbonate (1.096 g, 7.93 mmol) in DMF (20 mL). Thereaction mixture was left to stir at rt for 2 h. The reaction mixturewas concentrated under vacuum and partitioned between DCM (20 mL) andwater (20 mL). The organic layer was concentrated under vacuum, loadedin DCM (3 mL) and purified by Biotage Isolera SNAP 25 g silica flashchromatography using a gradient of 0-60% cyclohexane/ethyl acetate. Theappropriate fractions were combined and concentrated under vacuum togive the product (900 mg) as a white solid.

LCMS (2 min Formic): Rt=1.24 min, [MH]⁺=375.1.

Intermediate 129:1-(4-Fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Butyl1-(4-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(900 mg, 2.404 mmol) was taken up in THF (10 mL) and water (10 mL).Lithium hydroxide (115 mg, 4.81 mmol) was added to the solution and thereaction stirred overnight at rt. 2M aq. HCl (3.61 mL, 7.21 mmol) wasadded and the resulting solid was washed with water to give the product(1 g) as a white solid.

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=319.0.

Intermediate 130: Butyl1-(3-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

1-(Bromomethyl)-3-fluorobenzene (0.729 mL, 5.95 mmol) was added to astirred suspension of butyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1 g, 3.96mmol) and potassium carbonate (1.096 g, 7.93 mmol) in DMF (20 mL). Thereaction mixture was stirred at rt for 1 h and partitioned between ethylacetate (40 mL) and water (40 mL). The organic layer was washed withwater (2×40 mL). This was passed through a hydrophobic frit and thesolvent removed under reduced pressure. The resulting yellow oil wasdissolved in DCM and purified by 100 g Biotage SNAP silica column usinga gradient of 0-75% ethyl acetate/cyclohexane. The clean,product-containing fractions were combined and the solvent removed underreduced pressure. The product was left to dry in vacuo for 2 h to givebutyl1-(3-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(1.23 g, 3.41 mmol, 86% yield) as a white solid.

LCMS (2 min Formic): Rt=1.16 min, [MH]⁺=361.1.

Intermediate 131:1-(3-Fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Sodium hydroxide (3.41 mL, 2.5 M, 8.53 mmol) in water was added to astirred solution of butyl1-(3-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(1.23 g, 3.41 mmol) in methanol (10 mL) and THF (10 mL). The reactionmixture was stirred at rt for 1 h and left to stand overnight. Thereaction mixture was neutralised to pH 7 with 2M HCl and the solventremoved under reduced pressure. This was partitioned between ethylacetate (40 mL) and water (40 mL) and the organic layer extracted withwater (2×40 mL); the aqueous layer was placed in a round-bottomed flaskand the solvent removed under reduced pressure. The solid was left todry in vacuo for 3 h to give1-(3-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (1.252 g, 3.29 mmol, 96% yield) as a white solid with 12 mol % NaClimpurity. Impurity carried forward in further synthesis.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=305.0.

Intermediate 132:5-Bromo-1-(2-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

1-(Bromomethyl)-2-fluorobenzene (0.392 mL, 3.25 mmol) was added to asuspension of 5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(500 mg, 2.164 mmol) and potassium carbonate (598 mg, 4.33 mmol) in DMF(8 mL). The reaction mixture was stirred at rt under nitrogen for 2 h,partitioned between ethyl acetate and water and the organic layer washedwith 2× water. The organic layer was passed through a hydrophobic fritand the solvent removed under reduced pressure. The yellow oil wasdissolved in DCM and loaded onto a 50 g Biotage SNAP column which waseluted in cyclohexane:ethyl acetate (0-75%). The product-containingfractions were combined and the solvent removed under reduced pressure.The product was left to dry in vacuo overnight to give the product(536.3 mg) as a pale yellow solid.

LCMS (2 min Formic): Rt=0.98 min, [MH]⁺=338.9 & 340.9

Intermediate 133: Methyl1-(4-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

1-(Bromomethyl)-4-fluorobenzene (0.207 mL, 1.665 mmol) was added to asolution of methyl5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (350 mg,1.665 mmol) and potassium carbonate (460 mg, 3.33 mmol), in DMF (15 mL).The reaction mixture was left to stir at rt for 2 h. The reactionmixture was concentrated under vacuum and separated between DCM (20 mL)and water (20 mL). The organic solution was concentrated under vacuum,loaded in DCM (3 mL) and purified by Biotage Isolera SNAP 25 g silicaflash chromatography using a gradient of 0-60% cyclohexane/ethylacetate. The appropriate fractions were combined and concentrated undervacuum to give the product (428 mg) as a white solid.

LCMS (2 min Formic): Rt=0.92 min, [MH]⁺=319.0.

Intermediate 134:1-(4-Fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Methyl1-(4-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(330 mg, 1.037 mmol) was taken up in THF (4 mL) and water (4.00 mL).Lithium hydroxide (49.7 mg, 2.074 mmol) was added to the solution andthe reaction stirred overnight at rt. 2M aq. HCl (1.555 mL, 3.11 mmol)was added and the reaction mixture partitioned between water (10 mL) and10% MeOH/DCM (10 mL). The aqueous layer was washed further with 10%MeOH/DCM (2×10 mL). The organic layers were combined, passed through ahydrophobic frit and concentrated under vacuum to give the product(123.5 mg) as a white solid.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=305.0.

Intermediate 135:N5-Cyclopropyl-1-(3-formylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a stirred solution ofN5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(300 mg, 1.275 mmol) and potassium carbonate (353 mg, 2.55 mmol) in DMF(5.101 mL) under nitrogen at rt, was added 3-(bromomethyl)benzaldehyde(381 mg, 1.913 mmol) and the reaction stirred for 2 h. The reactionmixture was poured onto saturated aqueous lithium chloride (60 mL) atwhich point the product precipitated. The suspension was extracted withethyl acetate (150 mL, then 2×50 mL) to dissolve the poorly solubleprecipitate. The combined organics were washed with brine (2×20 mL),dried through a hydrophobic frit and evaporated in vacuo to yield thecrude product as a yellow oil (588 mg). The oil was dry loaded onto aSNAP cartridge (25 g) and purified via Biotage SP4 flash chromatography,eluting from 15-75% (3:1 ethyl acetate:ethanol)/cyclohexane. Therelevant fractions were combined and evaporated in vacuo to yield thedesiredproduct—N5-cyclopropyl-1-(3-formylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(369 mg, 0.992 mmol, 78% yield).

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=354.1.

Intermediate 136: (+/−)-(trans)-Methyl2-(2-(tert-butoxy)-2-oxoethyl)cyclopropanecarboxylate

A solution of diisopropylamine (5.70 mL, 40 mmol) in THF (25 mL) undernitrogen was treated at −78° C. with n-butyllithium (25 mL, 40.0 mmol,1.6M in hexanes). The resulting mixture was stirred for 5 min thenstirred at 0° C. for 30 min before being cooled again to −78° C. Thesolution was treated with the dropwise addition of tert-butyl acetate(5.37 mL, 40.0 mmol) in THF (10 mL) and the resulting mixture wasstirred at this temperature for 30 min before being treated with(E)-methyl 4-bromobut-2-enoate (7.16 g, 40 mmol, commercially availablefrom, for example, Sigma-Aldrich) in THF (15 mL). The mixture wasstirred for 1 h (orange solution) and an aliquot then taken which wasdiluted with DCM, washed with water, dried using a phase separator andconcentrated in vacuo. After, overall 1.5 h, the reaction mixture wastreated with a saturated NH₄Cl aqueous solution and warmed to rt. Themixture was partitioned between water and AcOEt and the layers wereseparated. The aqueous layer was extracted with AcOEt and the combinedorganics were washed with brine, dried over MgSO₄ and concentrated invacuo to give (+/−)-(trans)-methyl2-(2-(tert-butoxy)-2-oxoethyl)cyclopropanecarboxylate (8.30 g, 38.7mmol, 97% yield) as a yellow oil.

A solution of (+/−)-(trans)-methyl2-(2-(tert-butoxy)-2-oxoethyl)cyclopropanecarboxylate (8.30 g, 38.7mmol) contaminated with (E)-methyl 4-bromobut-2-enoate (25% by NMR) inmethanol (140 mL) was treated with palladium on carbon (1.5 g, 1.41mmol, 50% wet, 10% w/w) and the resulting mixture was stirred underhydrogen (1 bar) for 4 h. The palladium was then filtered off and rinsedwith AcOEt. Triethylamine (2.70 mL, 19.37 mmol) was added and themixture was concentrated in vacuo. The residue was partitioned betweenAcOEt and water and the layers were separated. The aqueous phase wasextracted with AcOEt and the combined organics were washed with brine,dried over MgSO₄ and concentrated in vacuo to give (+/−)-(trans)-methyl2-(2-(tert-butoxy)-2-oxoethyl)cyclopropanecarboxylate (7 g, 32.7 mmol,84% yield) as an orange/red oil which was used directly in the nextreaction.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.68 (s, 3H) 2.23 (d, J=7.1 Hz, 2H) 1.67(dqd, J=8.9, 6.8, 6.8, 6.8, 4.2 Hz, 1H) 1.43-1.53 (m, 10H) 1.23-1.29 (m,1H) 0.81 (ddd, J=8.3, 6.3, 4.5 Hz, 1H)

Intermediate 137:(+/−)-(trans)-2-(2-(tert-Butoxy)-2-oxoethyl)cyclopropanecarboxylic acid

A solution of (+/−)-(trans)-methyl2-(2-(tert-butoxy)-2-oxoethyl)cyclopropanecarboxylate (1071 mg, 5 mmol)in THF (15 mL) at rt was treated with NaOH (5 mL, 10.00 mmol, 2M aq.)and the resulting mixture stirred for 3 h. As it remained a biphasicmixture, MeOH (5 mL) was added and the reaction stirred o/n. The solventwas then concentrated in vacuo. The residue was dissolved in water andtreated with HCl (2N aq.) and then extracted with AcOEt twice. Thecombined organics were washed with brine, dried over MgSO₄ andconcentrated in vacuo to give, after trituration with Et₂O,(+/−)-(trans)-2-(2-(tert-butoxy)-2-oxoethyl)cyclopropanecarboxylic acid(720 mg, 3.60 mmol, 72% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 2.26 (ABq, J=7.1, 5.6 Hz, 2H) 1.70-1.83(m, 1H) 1.43-1.57 (m, 10H) 1.29-1.39 (m, 1H) 0.87-0.95 (m, 1H).Exchangeable proton not observed

Intermediate 138: (+/−)-tert-Butyl2-((trans)-2-(((benzyloxy)carbonyl)amino)cyclopropyl)acetate

A solution of(+/−)-(trans)-2-(2-(tert-butoxy)-2-oxoethyl)cyclopropanecarboxylic acid(720 mg, 3.60 mmol) in toluene (12 mL) was treated with triethylamine(1.50 mL, 10.79 mmol) then diphenyl phosphorazidate (0.930 mL, 4.32mmol), followed 2 min later by benzyl alcohol (0.748 mL, 7.19 mmol). Theresulting mixture was stirred at 110° C. and followed by LCMS. Bubblingoccurred extremely rapidly. After 4 h, the mixture was cooled to rt andconcentrated in vacuo. The residue was partitioned between EtOAc and asaturated NaHCO₃ aqueous solution, and the layers were separated. Theaqueous phase was then extracted with EtOAc and the combined organicswere washed with brine, dried over MgSO₄ and concentrated in vacuo.Purification of the crude product (ca. 1.6 g) was undertaken by flashchromatography on a Biotage SP4 (50 g silica column, 30% EtOAc/hexanes)to give (+/−)-tert-butyl2-((trans)-2-(((benzyloxy)carbonyl)amino)cyclopropyl)acetate (660 mg,2.16 mmol, 60% yield) as a yellow oil which was used without furtherpurification.

LCMS (2 min formic): Rt=1.20 min, [M+Na]⁺=328.2.

Intermediate 139: (+/−)-tert-Butyl 2-((trans)-2-aminocyclopropyl)acetate

A solution of (+/−)-tert-butyl2-((trans)-2-(((benzyloxy)carbonyl)amino)cyclopropyl)acetate (660 mg,2.16 mmol) in methanol (40 mL) at rt was treated with palladium oncarbon (150 mg, 0.14 mmol) (50% wet, 10% w/w) and the resulting mixturewas stirred under an atmosphere of hydrogen (1 bar) for 5 h. Thecatalyst was removed through a pad of celite and rinsed with methanol.The combined organics were concentrated in vacuo to give(+/−)-tert-butyl 2-((trans)-2-aminocyclopropyl)acetate (380 mg, 2.219mmol, 103% yield) as a pale yellow oil. Further experiments showed thatthis product was contaminated with the linear chain amine (in a 2:1ratio in favour of the desired product). This mixture was used crude inthe subsequent reaction

¹H NMR (400 MHz, CDCl₃) δ ppm 2.08-2.17 (m, 2H) 1.42-1.55 (m, 10H)0.92-1.05 (m, 1H) 0.54-0.62 (m, 1H) 0.34-0.42 (m, 1H). Exchangeableprotons not observed.

Intermediate 140:2-((1S,2S)-2-(Hydroxymethyl)cyclopropyl)isoindoline-1,3-dioneIntermediate 141:2-((1R,2R)-2-(Hydroxymethyl)cyclopropyl)isoindoline-1,3-dione

2-((trans)-2-(Hydroxymethyl)cyclopropyl)isoindoline-1,3-dione (3.2 g)was purified by chiral HPLC. The racemate (300 mg) was dissolved in EtOH(2 mL) with heat. Injection: 2 mL of the solution was injected onto thecolumn (50% EtOH/heptane, flow rate=30 mL/min, detection wavelength=215nm, 4. Ref 550, 100, Column 30 mm×25 cm Chiralpak AD-H (5 μm), lot no.ADH12143-01). Total number of injections=11. Fractions from 11-15.5 minwere bulked and labelled peak 1. Fractions from 18-28 min were bulkedand labelled peak 2. The bulked fractions were concentrated in vacuo andthen transferred to weighed flasks. Final compounds were recovered fromDCM and heptane in order to obtain a solid.

The fractions corresponding to peak 1 were collected to affordintermediate 140 (1.38 g)

LCMS (2 min formic): Rt=0.65 min, [M−OH]⁺=200.2.

The fractions corresponding to peak 2 were collected to affordintermediate 141 (1.36 g)

LCMS (2 min formic): Rt=0.65 min, [M−OH]⁺=200.2.

Intermediate 142:2-((1S,2S)-2-(Methoxymethyl)cyclopropyl)isoindoline-1,3-dione

2-((1S,2S)-2-(Hydroxymethyl)cyclopropyl)isoindoline-1,3-dione (200 mg,0.92 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (592 mg,2.76 mmol) were dissolved in DCM (8 mL). Trimethyloxoniumtetrafluoroborate (409 mg, 2.76 mmol) was added slowly and the reactionmixture was stirred under nitrogen for 1 h. The reaction mixture waspartitioned between DCM and water, the aqueous layer was then extractedwith DCM (2×20 mL), and the organic layer washed with water (20 mL) andsat. sodium bicarbonate solution (20 mL). This was passed through ahydrophobic frit and concentrated to ˜5 mL. The solution was purified byflash chromatography using a Biotage SNAP column (25 g) using a gradientof 0-100% ethyl acetate/cyclohexane. The product-containing fractionswere concentrated and the solvent removed in vacuo. The product wasdried under a stream of nitrogen to give2-((1S,2S)-2-(methoxymethyl)cyclopropyl)isoindoline-1,3-dione (193 mg,0.709 mmol, 77% yield) as a yellow solid.

LCMS (2 min formic): Rt=0.84 min, [MH]⁺=232.4.

Intermediate 143: (1S,2S)-2-(Methoxymethyl)cyclopropanamine,hydrochloride

Hydrazine hydrate (0.023 mL, 0.745 mmol) was added slowly to asuspension of2-((1S,2S)-2-(methoxymethyl)cyclopropyl)isoindoline-1,3-dione (193 mg,0.71 mmol) in ethanol (7 mL). The reaction mixture was heated to 40° C.under nitrogen for 2 days after which further hydrazine hydrate (0.023mL, 0.75 mmol) was added. The reaction mixture was heated to 50° C.under nitrogen overnight and further hydrazine hydrate (0.023 mL, 0.75mmol) was added. Heating was continued under nitrogen for 4 h. Thesuspension was cooled in an ice bath, filtered, and washed with ethanol.The filtrate was acidified to pH 1 with 2M HCl and the solventconcentrated to ˜10 mL. The white precipitate was filtered off andwashed with DCM. The filtrate was placed in a round-bottomed flask andthe solvent concentrated to ˜3 mL. Some white precipitate was noticed soethyl acetate was added and the suspension was passed through ahydrophobic frit to filter off the remaining solid. The product was leftto dry under a stream of nitrogen to give crude(1S,2S)-2-(methoxymethyl)cyclopropanamine, HCl salt (106 mg, 0.51 mmol,71% yield) as an orange oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.37-3.43 (m, 1H) 3.33 (s, 3H) 3.28 (dd,J=10.4, 6.5 Hz, 1H) 2.57-2.65 (m, 1H) 1.75-1.85 (m, 1H) 1.27-1.35 (m,1H) 0.81-0.89 (m, 1H). No exchangeable protons observed.

Intermediate 144:(1S,2S)-2-(1,3-Dioxoisoindolin-2-yl)cyclopropanecarbaldehyde

2-((1S,2S)-2-(Hydroxymethyl)cyclopropyl)isoindoline-1,3-dione (287 mg,1.32 mmol) was stirred in DCM (10 mL) and Dess-Martin periodinane (616mg, 1.45 mmol) was added slowly under nitrogen. The reaction mixture wasstirred at rt under nitrogen for 90 min. The reaction mixture wasquenched with sodium thiosulfate solution (10% in water, 50 mL) andpartitioned between DCM and sat. sodium bicarbonate solution. Theorganic layer was washed with sat. sodium bicarbonate solution. (20 mL)and brine (20 mL) and passed through a hydrophobic frit. The solvent wasconcentrated to ˜5 mL in vacuo and the resulting oil was purified byflash chromatography using a 25 g Biotage SNAP column and a gradient of0-70% ethyl acetate/cyclohexane. The product containing fraction wasconcentrated and the product was left to dry under a stream of nitrogento give (1S,2S)-2-(1,3-dioxoisoindolin-2-yl)cyclopropanecarbaldehyde(235 mg, 1.092 mmol, 83% yield) as a white solid.

LCMS (2 min formic): Rt=0.75 min, [MH]⁺=216.4.

Intermediate 145:2-((1S,2R)-2-((Dimethylamino)methyl)cyclopropyl)isoindoline-1,3-dione

Sodium triacetoxyborohydride (370 mg, 1.75 mmol) was added to a solutionof (1S,2S)-2-(1,3-dioxoisoindolin-2-yl)cyclopropanecarbaldehyde (235 mg,1.09 mmol) and dimethylamine (2M in THF, 0.573 mL, 1.15 mmol) in DCM (6mL). The reaction mixture was stirred at rt under nitrogen for 90 min.The reaction mixture was quenched with sat. sodium bicarbonate solution.and extracted with DCM (2×20 mL). The organic layer was passed through ahydrophobic frit and concentrated to ˜5 mL. This was purified by flashchromatography using a 25 g Biotage SNAP column and a gradient of 0-75%(20% methanolic ammonia in DCM)/DCM. The product-containing fractionswere combined and the solvent removed in vacuo. The product was left todry under a stream of nitrogen to give2-((1S,2R)-2-((dimethylamino)methyl)cyclopropyl)isoindoline-1,3-dione(76.1 mg, 0.31 mmol, 29% yield) as a yellow oil.

LCMS (2 min High pH): Rt=0.81 min, [MH]⁺=245.3.

Intermediate 146: (1S,2R)-2-((Dimethylamino)methyl)cyclopropanamine,hydrochloride

Hydrazine hydrate (15 μL, 0.478 mmol) was added to a solution of2-((1S,2R)-2-((dimethylamino)methyl)cyclopropyl)isoindoline-1,3-dione(76 mg, 0.31 mmol) in ethanol (5 mL). The reaction mixture was heated to50° C. under nitrogen for 90 min, after which further hydrazine hydrate(15 μL, 0.48 mmol) was added and heating was continued under nitrogenovernight. The suspension was cooled in an ice bath, filtered, andwashed with ethanol. The filtrate was acidified to pH 1 with 2M HCl andthis was concentrated to ˜10 mL. The resulting white precipitate wasremoved by filtration and washed with ethanol, and the filtrateconcentrated to ˜5 mL. This was passed through a hydrophobic frit andleft to dry under a stream of nitrogen to give impure(1S,2R)-2-((dimethylamino)methyl)cyclopropanamine hydrochloride (95.8mg, 0.19 mmol, 61% yield) as a yellow solid. The crude product was of˜30% purity and was used without further purification in furthersynthesis.

Intermediate 147:2-((1R,2R)-2-(Ethoxymethyl)cyclopropyl)isoindoline-1,3-dione

Meerwein's reagent (525 mg, 2.76 mmol) was added slowly to a suspensionof 2-((1R,2R)-2-(hydroxymethyl)cyclopropyl)isoindoline-1,3-dione (200mg, 0.921 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (592mg, 2.76 mmol) in DCM (5 mL). The reaction mixture was stirred for 90min. The reaction mixture was then partitioned between DCM (20 mL) andwater (20 mL) and the aqueous layer was extracted with DCM (20 mL). Theorganic layer was washed with sat. sodium bicarbonate solution. (10 mL)and passed through a hydrophobic frit. The solvent was removed in vacuoand the resulting oil dissolved in DCM. This was purified by flashchromatography using a 10 g Biotage SNAP column and a gradient of 0-100%cyclohexane/ethyl acetate. The product-containing fractions werecombined and the solvent removed in vacuo. The resulting oil waspurified by MDAP (Formic) and the product-containing fractions wereconcentrated. The product was dried under a stream of nitrogen to give2-((1R,2R)-2-(ethoxymethyl)cyclopropyl)isoindoline-1,3-dione (145 mg,0.59 mmol, 64% yield) as a white solid.

LCMS (2 min formic): Rt=0.94 min, [MH]⁺=246.4.

Intermediate 148: (1R,2R)-2-(Ethoxymethyl)cyclopropanamine,hydrochloride

Hydrazine monohydrate (0.029 mL, 0.59 mmol) was added to a solution of2-((1R,2R)-2-(ethoxymethyl)cyclopropyl)isoindoline-1,3-dione (145 mg,0.59 mmol) in ethanol (8 mL). The reaction mixture was heated to 40° C.under nitrogen overnight, after which further hydrazine monohydrate(0.029 mL, 0.59 mmol) was added and the temperature was increased to 50°C. Heating was continued for 4 h. The reaction mixture was then cooledto rt, filtered, and washed with ethanol. The filtrate was acidified topH 1 with 2M HCl and the solvent concentrated to ˜10 mL. The resultingwhite precipitate was filtered off and washed with DCM. Further whiteprecipitate formed in the filtrate so this was passed through ahydrophobic frit and the solvent removed in vacuo. The product was leftto dry under a stream of nitrogen to give(1R,2R)-2-(ethoxymethyl)cyclopropanamine hydrochloride salt (160 mg,0.42 mmol, 71% yield) as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.70 (dd, J=10.3, 6.1 Hz, 1H) 3.55-3.63(m, 2H) 3.40 (dd, J=10.5, 6.8 Hz, 1H) 2.67 (dt, J=7.6, 3.8 Hz, 1H)1.70-1.81 (m, 1H) 1.23-1.32 (m, 4H) 1.04-1.11 (m, 1H). No exchangeableprotons observed.

Intermediate 149:2-((1S,2S)-2-(Ethoxymethyl)cyclopropyl)isoindoline-1,3-dione

Meerwein's reagent (350 mg, 1.84 mmol) was added slowly to a solution of2-((1S,2S)-2-(hydroxymethyl)cyclopropyl)isoindoline-1,3-dione (200 mg,0.92 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (395 mg,1.84 mmol) in DCM (5 mL). The reaction mixture was stirred at rt undernitrogen for 1 h. The reaction mixture was then partitioned between DCM(30 mL) and water (30 mL). The organic layer was washed with water (20mL) and sat. sodium bicarbonate solution. (20 mL), passed through ahydrophobic frit, and the solvent concentrated to ˜10 mL. This waspurified by flash chromatography using a 25 g Biotage SNAP column and agradient of 0-100% ethyl acetate/cyclohexane. The product-containingfractions were combined and the solvent removed in vacuo. The productwas left to dry under a stream of nitrogen overnight to give2-((1S,2S)-2-(ethoxymethyl)cyclopropyl)isoindoline-1,3-dione (188 mg,0.74 mmol, 80% yield) as a pale yellow solid.

LCMS (2 min formic): Rt=0.94 min, [MH]⁺=246.2.

Intermediate 150: (1S,2S)-2-(Ethoxymethyl)cyclopropanamine hydrochloride

Hydrazine hydrate (0.072 mL, 0.81 mmol) was added to a suspension of2-((1S,2S)-2-(ethoxymethyl)cyclopropyl)isoindoline-1,3-dione (188 mg,0.77 mmol) in ethanol (7 mL). The reaction mixture was heated to 40° C.under nitrogen for 6 h. The reaction mixture was then cooled in an icebath, filtered, and washed with cold ethanol. The filtrate was acidifiedto pH 1 with 2M HCl and the solvent concentrated to ˜5 mL. The remainingwhite precipitate was filtered off and washed with DCM, and the filtratewas placed in a round-bottomed flask. The solvent was removed in vacuoand significant amounts of white precipitate were observed. This wasfiltered off and washed with DCM, and the solvent of the filtrate wasremoved in vacuo. The product was left to dry under a stream of nitrogenfor 2 h to give (1R,2R)-2-(ethoxymethyl)cyclopropanamine, hydrochloridesalt (21 mg, 0.04 mmol, 5% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.70 (dd, J=10.5, 5.9 Hz, 1H) 3.55-3.64(m, 2H) 3.40 (dd, J=10.5, 6.6 Hz, 1H) 2.67 (dt, J=7.6, 3.8 Hz, 1H)1.70-1.80 (m, 1H) 1.22-1.32 (m, 4H) 1.04-1.11 (m, 1H). No exchangeableprotons observed.

Intermediate 151:(±)-2-((trans)-2-(Methoxymethyl)cyclopropyl)isoindoline-1,3-dione

(±)-2-((trans)-2-(Hydroxymethyl)cyclopropyl)isoindoline-1,3-dione (150mg, 0.69 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (443mg, 2.07 mmol) were dissolved in DCM (7 mL) and trimethyloxoniumtetrafluoroborate (320 mg, 2.16 mmol) was added slowly, the reaction wasstirred under N₂ at rt. After 30 min the suspension was partitionedbetween DCM (20 mL) and water (20 mL), extracted with DCM (2×20 mL),dried over a hydrophobic frit and concentrated to give 520 mg of ayellow solid. This was purified by chromatography on SiO₂ (Biotage SNAP50 g cartridge, eluting with 0-50% ethyl acetate/cyclohexane). Thedesired fractions were concentrated to give(±)-2-((trans)-2-(methoxymethyl)cyclopropyl)isoindoline-1,3-dione (62mg, 0.24 mmol, 35% yield).

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=232.2.

Intermediate 152: (±)-(trans)-2-(Methoxymethyl)cyclopropanaminehydrochloride

(±)-2-((trans)-2-(Methoxymethyl)cyclopropyl)isoindoline-1,3-dione (68mg, 0.29 mmol) was added to methylamine (33% in ethanol, 0.5 mL, 4.02mmol) and the solution was then heated at 120° C. in a microwave for 1h. A white precipitate had formed, this was filtered under vacuum. Thefiltrate was evaporated in vacuo (250 mbar, rt). 4 M HCl in dioxane(1.25 mL, 5.00 mmol) was added, this was concentrated to give(±)-(trans)-2-(methoxymethyl)cyclopropanamine, hydrochloride (147 mg,0.267 mmol, 91% yield) as a white crystalline solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.35 (br. s., 3H) 3.27-3.33 (m, 1H) 3.24(s, 3H) 3.13 (dd, J=10.5, 7.1 Hz, 1H) 2.41-2.47 (m, 1H) 1.44 (td, J=6.6,3.7 Hz, 1H) 0.93 (ddd, J=9.8, 5.7, 4.0 Hz, 1H) 0.66 (dt, J=7.6, 6.0 Hz,1H)

Intermediate 153:2-((1R,2R)-2-(Methoxymethyl)cyclopropyl)isoindoline-1,3-dione

2-((1R,2R)-2-(Hydroxymethyl)cyclopropyl)isoindoline-1,3-dione (205 mg,0.94 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (602 mg,2.81 mmol) were dissolved in DCM (10 mL) and trimethyloxoniumtetrafluoroborate (410 mg, 2.77 mmol) was added slowly, the reaction wasstirred under N₂ at rt. After 1.5 h, the suspension was partitionedbetween DCM (20 mL) and water (20 mL), extracted with DCM (2×20 mL),dried over a hydrophobic frit and concentrated to give the crude product(863 mg) as a yellow solid. This was purified by chromatography on SiO₂(Biotage SNAP 50 g cartridge, eluting with 0-50% ethylacetate/cyclohexane). The desired fractions were concentrated to give2-((1R,2R)-2-(methoxymethyl)cyclopropyl)isoindoline-1,3-dione (193 mg,0.75 mmol, 80% yield) as a white solid.

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=232.4.

Intermediate 154: (1R,2R)-2-(Methoxymethyl)cyclopropanamine,hydrochloride

Hydrazine hydrate (0.043 mL, 0.88 mmol) was added slowly to a suspensionof 2-((1R,2R)-2-(methoxymethyl)cyclopropyl)isoindoline-1,3-dione (194mg, 0.84 mmol) in ethanol (7 mL). The reaction mixture was heated to 50°C. under N₂ overnight. The white precipitate was filtered under vacuum.The filtrate was acidified to pH 1 with 4M HCl in dioxane (5 mL, 20.00mmol) and concentrated to give(1R,2R)-2-(methoxymethyl)cyclopropanamine, hydrochloride (240 mg, 0.84mmol, 100% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.33 (br. s., 3H) 3.30 (dd, J=10.5, 6.1Hz, 1H) 3.24 (s, 3H) 3.13 (dd, J=10.6, 7.2 Hz, 1H) 2.45 (dd, J=8.1, 3.7Hz, 1H) 1.44 (dt, J=6.4, 3.4 Hz, 1H) 0.92 (ddd, J=9.8, 5.7, 4.0 Hz, 1H)0.67 (dt, J=7.6, 6.1 Hz, 1H)

Intermediate 155: (+/−)-2-((trans)-2-(Methoxycarbonyl)cyclopropyl)aceticacid

A solution of (+/−)-(trans)-methyl2-(2-(tert-butoxy)-2-oxoethyl)cyclopropanecarboxylate (321 mg, 1.50mmol) in DCM (2 mL) at 0° C. was treated with TFA (2 mL) dropwise andthe resulting mixture was stirred at this temperature for 1.5 h. Analiquot was concentrated in vacuo and showed complete conversion. Theremaining solution was concentrated in vacuo and co-evaporated with Et₂Othen DCM to give (+/−)-2-((trans)-2-(methoxycarbonyl)cyclopropyl)aceticacid (200 mg, 1.27 mmol, 84% yield) as a very pale brown oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.72 (s, 3H) 2.40-2.46 (m, 2H) 1.71-1.81(m, 1H) 1.55-1.61 (m, 1H) 1.31-1.37 (m, 1H) 0.85-0.92 (m, 1H). Noexchangeable proton observed.

Intermediate 156: (+/−)-(trans)-Methyl2-(2-hydroxyethyl)cyclopropanecarboxylate

A solution of (+/−)-2-((trans)-2-(methoxycarbonyl)cyclopropyl)aceticacid (967 mg, 6.11 mmol) in THF (20 mL) at 0° C. was treated with boranetetrahydrofuran complex (1M in THF, 15.29 mL, 15.29 mmol) and theresulting mixture was stirred at this temperature for 1.5 h. Afteroverall 2 h, the resulting mixture was treated with methanol (4.95 mL,122.0 mmol) and after 5 min, concentrated in vacuo. Purification of thisresidue by SP4 flash chromatography was undertaken, using a 50 g silicacolumn and eluting with a 50% GLOBAL gradient (AcOEt in hexanes) to giveafter concentration in vacuo—(+/−)-(trans)-methyl2-(2-hydroxyethyl)cyclopropanecarboxylate (1.6 g, 11.10 mmol, 60% yield)as a colourless oil then a further batch of (+/−)-(trans)-methyl2-(2-hydroxyethyl)cyclopropanecarboxylate (404 mg, 2.80 mmol, 15% yield)

¹H NMR (400 MHz, CDCl₃) δ ppm 3.74 (t, J=6.5 Hz, 2H) 3.65-3.69 (m, 3H)1.51-1.67 (m, 2H) 1.40-1.50 (m, 2H) 1.17-1.24 (m, 1H) 0.73-0.81 (m, 1H).No exchangeable proton observed.

Intermediate 157: (+/−)-(trans)-Methyl2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropanecarboxylate

A solution of (+/−)-(trans)-methyl2-(2-hydroxyethyl)cyclopropanecarboxylate (404 mg, 2.80 mmol) in DCM (15mL) at rt was treated with imidazole (286 mg, 4.20 mmol) then TBDMS-Cl(507 mg, 3.36 mmol) then DMAP (34.2 mg, 0.28 mmol) and the resultingmixture was stirred at this temperature for 16 h. A white precipitateformed very quickly. The mixture was diluted with DCM and water and thelayers were separated. The aqueous phase was extracted with DCM and thecombined organics were dried using a phase separator then wereconcentrated in vacuo to give (+/−)-(trans)-methyl2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropanecarboxylate (724mg, 2.80 mmol, 100% yield) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.65-3.71 (m, 5H) 1.39-1.59 (m, 4H)1.14-1.21 (m, 1H) 0.90 (s, 9H) 0.71-0.77 (m, 1H) 0.05 (s, 6H)

Intermediate 158:(+/−)-(trans)-2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)cyclopropanecarboxylicacid

A solution of (+/−)-(trans)-methyl2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropanecarboxylate (724mg, 2.80 mmol) in methanol (8 mL) at rt was treated with NaOH (2.80 mL,5.60 mmol, 2N in water) and the resulting mixture was stirred at thistemperature for 16 h before being concentrated in vacuo. The residue waspartitioned between AcOEt and water and the mixture was treated with HCl(2.80 mL, 5.60 mmol, 2M aq.). The layers were separated and the aqueousphase was extracted with EtOAc. The combined organics were dried overMgSO₄ and concentrated in vacuo to give(+/−)-(trans)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropanecarboxylicacid (549 mg, 2.25 mmol, 80% yield) as a pale yellow solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.66-3.72 (m, 2H) 1.51-1.56 (m, 3H) 1.42(ddd, J=8.2, 4.6, 3.5 Hz, 1H) 1.21-1.29 (m, 1H) 0.90 (s, 9H) 0.81-0.86(m, 1H) 0.06 (s, 6H). No exchangeable proton observed.

Intermediate 159: (+/−)-Benzyl((trans)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)carbamate

A solution of(+/−)-(trans)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropanecarboxylicacid (2.31 g, 9.45 mmol) in toluene (40 mL) was treated withtriethylamine (3.95 mL, 28.4 mmol) then diphenyl phosphorazidate (2.444mL, 11.34 mmol), followed 2 min later by benzyl alcohol (1.966 mL, 18.90mmol). The resulting mixture was stirred at 110° C. After 6 h, themixture was cooled to rt and concentrated in vacuo. The residue waspartitioned between EtOAc and water, and the layers were separated. Theaqueous phase was extracted with EtOAc and the combined organics werewashed with brine, dried over MgSO₄ and concentrated in vacuo.Purification of the crude (ca. 4 g) by SP4 flash chromatography wasunderaken, using a 100 g silica column, and eluting with a 50% GLOBALgradient (EtOAc in hexanes) to give after concentration in vacuo,(+/−)-benzyl((trans)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)carbamate(1.57 g, 4.49 mmol, 48% yield) as a yellow oil.

LCMS (2 min High pH): Rt=1.55 min, [MH]⁺=350.3.

Intermediate 160:(+/−)-(trans)-2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)cyclopropanamine

A solution of (+/−)-benzyl((trans)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)carbamate(1.4 g, 4.01 mmol) in methanol (30 mL) at rt was treated with palladiumon carbon (300 mg, 0.28 mmol, 10% w/w, 50% wet) and the resultingsuspension was stirred at this temperature under an atmosphere ofhydrogen (1 bar) for 16 h. The catalyst was filtered off and rinsed withmethanol. The combined organics were concentrated in vacuo to give(+/−)-(trans)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropanamine(920 mg, 4.27 mmol, 107% yield) as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.64-3.67 (m, 2H) 1.40-1.55 (m, 2H) 1.33(dt, J=13.6, 6.8 Hz, 1H) 0.91 (s, 9H) 0.70-0.77 (m, 1H) 0.45-0.51 (m,1H) 0.29 (dt, J=6.8, 5.3 Hz, 1H) 0.07 (s, 6H). No exchangeable protonsobserved.

Intermediate 161: (1H-Pyrrolo[3,2-c]pyridin-4-yl)methanol, hydrochloride

To a solution of 1H-pyrrolo[3,2-c]pyridine-4-carboxylic acid (400 mg,2.47 mmol, commercially available from, for example, Sigma-Aldrich) inTHF (16 mL), was added borane tetrahydrofuran complex (1 M in THF, 4.93mL, 4.93 mmol) at rt. The reaction was stirred at rt for 3 h. Thereaction was then quenched with methanol (0.998 mL, 24.67 mmol) andhydrochloric acid (1M, 3.08 mL, 6.17 mmol) and stirred for 1 h at rt.The reaction mixture was left to stand overnight. A precipitate wasnoted in the reaction mixture which was filtered off to yield(1H-pyrrolo[3,2-c]pyridin-4-yl)methanol, hydrochloride (306 mg, 1.33mmol, 54% yield) as an off-white solid which was used without furtherpurification.

LCMS (2 min High pH): Rt=0.43 min, [MH]⁺=149.1.

Intermediate 162: Methyl 2-methyl-1H-indole-4-carboxylate

To sulfuric acid (0.127 mL, 2.26 mmol) in methanol (20.8 mL) was added2-methyl-1H-indole-4-carboxylic acid (400 mg, 2.28 mmol, commerciallyavailable from, for example, Apollo Scientific) and the reaction washeated under reflux (65° C.) for 18 h. The reaction mixture was thenneutralized with sodium bicarbonate, evaporated in vacuo and taken up indichloromethane (40 mL). The organic layer was washed with water (20 mL)and the aqueous layer was back extracted with dichloromethane (2×20 mL).The organic layer was dried through a hydrophobic frit and evaporated invacuo to yield the desired product as an orange solid—methyl2-methyl-1H-indole-4-carboxylate (430 mg, 2.16 mmol, 95% yield).

LCMS (2 min formic): Rt=0.94 min, [MH]⁺=190.2.

Intermediate 163: Methyl 2-methyl-1-tosyl-1H-indole-4-carboxylate

Methyl 2-methyl-1H-indole-4-carboxylate (430 mg, 2.273 mmol) wasdissolved in DMF (5.7 mL) at 0° C. under nitrogen. Sodium hydride (60%dispersion in mineral oil, 136 mg, 3.41 mmol) was added in portions. Thereaction was stirred at 0° C. for 10 min before warming to rt andstirring for 30 min. Tosyl-Cl (563 mg, 2.95 mmol) was added and thereaction mixture was stirred at rt. Upon completion, the reaction wascooled to 0° C. and quenched with water (8 mL). A precipitate was notedin the reaction mixture which was filtered off and washed with water(2×10 mL). The solid was dried in vacuo to yield methyl2-methyl-1-tosyl-H-indole-4-carboxylate (680 mg, 1.88 mmol, 83% yield)as a brown solid.

LCMS (2 min formic): Rt=1.36 min, [MH]⁺=344.1.

Intermediate 164: (2-Methyl-1-tosyl-1H-indol-4-yl)methanol

A solution of methyl 2-methyl-1-tosyl-1H-indole-4-carboxylate (675 mg,1.97 mmol) in DCM (9.8 mL) under nitrogen was cooled to −78° C. andDIBAL-H (2.34 M in toluene, 3.70 mL, 8.65 mmol) was added dropwise over30 min and the reaction was stirred at −78° C. for 2 h. The reaction wasthen quenched with methanol (795 μL, 19.66 mmol) when still at −78° C.and then allowed to warm to ambient temperature. The reaction wasdiluted with Rochelle's salt solution (50 mL) and stirred for 16 h. Thelayers were separated and the aqueous layer was extracted withdichloromethane (3×20 mL). The combined organics were dried through ahydrophobic frit and evaporated in vacuo to yield the crude product as abrown oil (692 mg). The sample was loaded in dichloromethane onto a 25 gSNAP cartridge and purified via Biotage SP4 flash chromatography elutingwith 15-65% ethyl acetate/cyclohexane. The relevant fractions werecombined and evaporated in vacuo to yield the desired product(2-methyl-1-tosyl-1H-indol-4-yl)methanol (535 mg, 1.61 mmol, 82% yield)as a colourless gum.

LCMS (2 min formic): Rt=1.12 min, [MH]⁺=316.1.

Intermediate 165: 4-(Bromomethyl)-2-methyl-1-tosyl-1H-indole

(2-Methyl-1-tosyl-1H-indol-4-yl)methanol (254 mg, 0.81 mmol) wasdissolved in DCM (1611 μL) and stirred at 0° C. under N₂. PBr₃ (114 μL,1.21 mmol) was added dropwise and the reaction stirred at 0° C. for 1 h.The reaction was then quenched with aqueous sodium bicarbonate (1 mL),poured onto water (25 mL) and extracted with dichloromethane (3×25 mL).The combined organics were dried through a hydrophobic frit andevaporated in vacuo to yield the crude product4-(bromomethyl)-2-methyl-1-tosyl-1H-indole (351 mg, 0.56 mmol, 69.1%yield) as a purple gum.

LCMS (2 min formic): Rt=1.40 min, [MH]⁺=378.1, 380.0.

Intermediate 166: Quinolin-7-ylmethanol

To quinoline-7-carboxylic acid (200 mg, 1.16 mmol, commerciallyavailable from, for example, Fluorochem) in THF (1 mL), boranetetrahydrofuran complex (1M in THF, 3.46 mL, 3.46 mmol) was added andthe reaction stirred at rt for 1 h. The reaction was then diluted withEtOAc (10 mL), washed with NaHCO₃ solution (10 mL), the aqueous layerwas extracted with EtOAc (2×10 mL), the organic layers were dried over ahydrophobic frit and concentrated to give 271 mg of a yellow oil. Thiswas purified by flash chromatography on SiO₂ (Biotage SNAP 25 gcartridge, eluting with 0-100% EtOAc/cyclohexane), the appropriatefractions were concentrated to give quinolin-7-ylmethanol (140 mg, 0.79mmol, 69% yield) as a yellow solid.

LCMS (2 min formic): Rt=0.71 min, [MH]⁺=160.1.

Intermediate 167: 7-(Bromomethyl)quinoline

A solution of quinolin-7-ylmethanol (63 mg, 0.40 mmol) in HBr (48% inwater, 1 mL, 8.84 mmol) was heated to 80° C. for 2.5 h. The reactionmixture was then evaporated in vacuo to yield the crude product7-(bromomethyl)quinoline (115 mg, 0.26 mmol, 65% yield, 50% purity) as abrown solid. This was used crude in the next reaction.

LCMS (2 min formic): Rt=0.60 min, [MH]⁺=222.1, 224.1.

Intermediate 168: 1-(1-Bromoethyl)-3-methoxybenzene

1-(3-Methoxyphenyl)ethanol (1000 mg, 6.57 mmol, commercially availablefrom, for example, Enamine) was dissolved in DCM (6.6 mL) and stirred at0° C. under N₂. PBr₃ (273 μL, 2.89 mmol) was added dropwise and thereaction stirred at 0° C. for 1.5 h. A further portion of PBr₃ (62.0 μL,0.657 mmol) was added and the reaction warmed to rt and stirredovernight. The reaction was cooled back down to 0° C. and a furtherportion of PBr₃ (186 μL, 1.971 mmol) was added. After 18.5 h thereaction was quenched with water (3 mL), neutralized with sodiumbicarbonate and diluted up to 50 mL with water. The aqueous layer wasextracted with DCM (3×20 mL), dried through a hydrophobic frit andevaporated in vacuo to give 1-(1-bromoethyl)-3-methoxybenzene (1384 mg,5.79 mmol, 88% yield) as a colourless oil.

LCMS (2 min formic): Rt=1.18 min, does not ionise at correct [MH]⁺

Intermediate 169: 2-(3-(Bromomethyl)phenyl)ethanol

Borane tetrahydrofuran complex (1M in THF, 4.37 mL, 4.37 mmol) was addeddropwise to a THF (20 mL) solution of 2-(3-(bromomethyl)phenyl)aceticacid (500 mg, 2.18 mmol, commercially available from, for example,Fluorochem) at 0° C. The mixture was allowed to warm to rt and stirredfor 2 h. Excess reagent was quenched by the slow addition of MeOH at 0°C. The reaction mixture was concentrated in vacuo, loaded in DCM andpurified by Biotage Isolera flash chromatography, using a SNAP 25 gsilica cartridge and eluting with a gradient of 0-100% EtOAc/cyclohexaneto give after concentration in vacuo 2-(3-(bromomethyl)phenyl)ethanol(440 mg, 2.05 mmol, 94% yield) as a brown residue.

LCMS (2 min Formic): Rt=0.87 min, [MH]⁺=216

Intermediate 170: Methyl 1-tosyl-1H-pyrrolo[3,2-c]pyridine-4-carboxylate

A solution of methyl 1H-pyrrolo[3,2-c]pyridine-4-carboxylate (501.7 mg,2.85 mmol; commercially available from, for example, Matrix Scientific)in DMF (10 mL) was cooled to approx. 0° C. in an ice bath undernitrogen. To this stirring mixture was added sodium hydride (60%dispersion in mineral oil, 179.1 mg, 4.48 mmol) portionwise to afford abright yellow solution. This was stirred at 0° C. for approx. 10 min,after which 4-toluenesulfonyl chloride (700.1 mg, 3.67 mmol) was added.The mixture was allowed to warm to rt while stirring and was stirred fora further 2.25 h. To the reaction mixture was added water (10 mL) and itwas stirred for a further 5 min. To this mixture was added sat. aqueouslithium chloride (25 mL) and water (25 mL). The resulting cloudy yellowsolution was extracted with ethyl acetate (3×50 mL). The organic phaseswere combined and filtered through a cartridge fitted with a hydrophobicfrit. The filtrate was evaporated in vacuo to give a light yellow solid;methyl 1-tosyl-1H-pyrrolo[3,2-c]pyridine-4-carboxylate (837.9 mg, 2.54mmol, 89% yield).

LCMS (2 min high pH) Rt=1.07 min, m/z=331 for [MH]⁺

¹H NMR (400 MHz, CDCl₃) δ ppm 8.62 (d, J=5.4 Hz, 1H) 8.09 (dd, J=5.6,0.7 Hz, 1H) 7.79 (d, J=8.3 Hz, 2H) 7.73 (d, J=3.7 Hz, 1H) 7.42 (d, J=3.2Hz, 1H) 7.24-7.31 (m, 2H) 4.04 (s, 3H) 2.37 (s, 3H)

Intermediate 171: (1-Tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)methanol

A mixture of methyl 1-tosyl-1H-pyrrolo[3,2-c]pyridine-4-carboxylate(836.7 mg, 2.53 mmol) and calcium chloride (560.1 mg, 5.05 mmol) inethanol (10.0 mL) and 2-methyltetrahydrofuran (10.0 mL) was cooled to 0°C. in an ice bath while stirring under nitrogen. To this mixture wasadded sodium borohydride (148.1 mg, 3.91 mmol) portionwise, after whichthe mixture was removed from the ice bath and allowed to warm to rt. Themixture was stirred at rt for 28 h. The reaction mixture was warmed to40° C. and stirred for a further 19 h before being allowed to cool tort. To the mixture was added sat. aqueous ammonium chloride (10 mL) andthe mixture stirred for 10 min. The resulting mixture was concentratedin vacuo to remove the organic solvents. To this was added brine (10mL), water (25 mL) and ethyl acetate (30 mL) and the layers separated.The aqueous layer was extracted with ethyl acetate (2×30 mL) and thecombined organic phases combined and washed with water (2×30 mL). Theorganic phase was filtered through a cartridge fitted with a hydrophobicfrit and the cartridge washed with methanol (approx. 50 mL) anddichloromethane (approx. 30 mL). The filtrate was evaporated in vacuo togive a white solid which was suspended in methanol and directly appliedto the top of a 20 g Isolute aminopropyl ion exchange column. The columnwas eluted with 6 column volumes of methanol. The required fractionswere combined and evaporated under a stream of nitrogen to give a glassyorange solid; (1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)methanol (605.2 mg,1.60 mmol, 63% yield).

LCMS (2 min high pH) Rt=0.94 min, m/z=303 for [MH]⁺

¹H NMR (400 MHz, CDCl₃) δ ppm 8.42 (d, J=5.9 Hz, 1H) 7.84 (d, J=5.9 Hz,1H) 7.80 (d, J=8.3 Hz, 2H) 7.62 (d, J=3.7 Hz, 1H) 7.26-7.31 (m, 2H) 6.71(d, J=3.2 Hz, 1H) 4.95 (s, 2H) 4.23 (br. s., 1H) 2.38 (s, 3H)

Intermediate 172: tert-Butyl3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

To a suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (304 mg,2.08 mmol; commercially available from, for example, Enamine) anddi-tert-butyl dicarbonate (0.580 mL, 2.50 mmol) in acetonitrile (5 mL)was added DMAP (28 mg, 0.23 mmol) and the reaction mixture stirred at rtunder nitrogen for 6.5 h before being left to stand overnight. Thereaction mixture was concentrated in vacuo to give a brown solid whichwas dissolved in dichloromethane (3 mL) and loaded onto a 25 g SNAPsilica cartridge and purified by flash chromatography eluting with agradient of 30-50% ethyl acetate in cyclohexane. The required fractionswere combined and concentrated in vacuo before the residue was dissolvedin dichloromethane (6 mL), transferred to a tarred vial, concentratedunder a stream of nitrogen and dried in vacuo to give a white solid;tert-butyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (420.7 mg,1.71 mmol, 82% yield).

LCMS (2 min high pH) Rt=0.97 min, m/z=247 for [MH]⁺

Intermediate 173: tert-Butyl3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

A solution of tert-butyl3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (420 mg, 1.71 mmol) inethanol (10 mL) was cooled to 0° C. with stirring under nitrogen beforesodium borohydride (126.6 mg, 3.35 mmol) was added. The reaction mixturewas allowed to warm to rt and stirred for 1.25 h. An aqueous solution ofhydrochloric acid (2 M, 4 drops) was added, followed immediately by asaturated solution of sodium bicarbonate (1 mL). The reaction mixturewas concentrated in vacuo and the residue partitioned between saturatedaqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL).The phases were separated and the aqueous phase further extracted withethyl acetate (2×50 mL). The organic phases were combined, filteredthrough a cartridge containing a hydrophobic frit and the solventevaporated in vacuo. The residue was dissolved in a 1:1 mixture ofdichloromethane/methanol (10 mL), concentrated under a stream ofnitrogen, and dried in vacuo to give a white solid which was dissolvedin dichloromethane (5 mL) and loaded onto a 25 g SNAP silica cartridgewhich was purified by flash chromatography, eluting with a gradient of50-100% ethyl acetate in cyclohexane. The required fractions wereconcentrated in vacuo before being dissolved in a 1:1 mixture ofdichloromethane/methanol (10 mL), transferred to a tarred vial,concentrated under a stream of nitrogen and dried in vacuo to give awhite solid; tert-butyl3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (199.7 mg,0.80 mmol, 47% yield).

LCMS (2 min formic) Rt=0.72 min, m/z=249 for [MH]⁺

Intermediate 174:1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indole-3-carbaldehyde

To a suspension of 1H-indole-3-carbaldehyde (49.7 mg, 0.34 mmol,commercially available from, for example, Sigma-Aldrich) and potassiumcarbonate (72.7 mg, 0.53 mmol) in DMF (2 mL) was added(2-bromoethoxy)(tert-butyl)dimethylsilane (0.088 mL, 0.41 mmol;commercially available from, for example, Sigma-Aldrich) and thereaction mixture was stirred at 80° C. under nitrogen for 20.5 h. Thereaction mixture was left to cool to rt and left standing for 2 days.Saturated aqueous sodium bicarbonate (10 mL) was added and the mixtureextracted with ethyl acetate (10 mL). The phases were separated and theaqueous phase further extracted with ethyl acetate (2×10 mL). Theorganic phases were combined, filtered through a cartridge containing ahydrophobic frit and concentrated in vacuo. The residue was dissolved indichloromethane (5 mL), transferred to a tarred vial, concentrated undera stream of nitrogen and dried in vacuo to give an orange oil. The oilwas dissolved in dichloromethane (3 mL) and loaded onto a 10 g SNAPsilica cartridge which was eluted with a gradient of 20-70% ethylacetate in cyclohexane. The required fractions were concentrated invacuo before being dissolved in dichloromethane (6 mL), transferred to atarred vial, concentrated under a stream of nitrogen and dried in vacuoto give a yellow oil;1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole-3-carbaldehyde (98.8mg, 0.33 mmol, 95% yield).

LCMS (2 min formic) Rt=1.38 min, m/z=304 for [MH]⁺

Intermediate 175:(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)methanol

A solution of1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole-3-carbaldehyde (97.5mg, 0.32 mmol) in ethanol (2 mL) was cooled to 0° C. with stirring undernitrogen before sodium borohydride (25 mg, 0.66 mmol) was added. Thereaction mixture was allowed to warm to rt and stirred for 6 h. Water (3mL) was added and the reaction mixture partitioned between aqueoussaturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL).The phases were separated and the aqueous phase extracted with furtherethyl acetate (2×10 mL). The organic phases were combined, filteredthrough a cartridge containing a hydrophobic frit and concentrated invacuo. The resulting oil was dissolved in a 1:1 mixture ofdichloromethane/methanol (6 mL), transferred to a tarred vial,concentrated under a stream of nitrogen and dried in vacuo to give ayellow oil;(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)methanol (88.5mg, 0.29 mmol, 90% yield).

¹H NMR (400 MHz, CDCl₃) δ ppm 7.74 (d, J=8.1 Hz, 1H) 7.36 (d, J=8.1 Hz,1H) 7.25 (dt, J=7.1 Hz, 1.2 Hz, 1H) 7.18 (s, 1H) 7.16 (dt, J=7.1 Hz, 1.0Hz, 1H) 4.88 (d, J=4.9 Hz, 2H) 4.23 (t, J=5.6 Hz, 2H) 3.93 (t, J=5.6 Hz,2H) 1.37 (br t, J=5.4 Hz 1H) 0.86 (s, 9H) −0.09 (2, 6H).

Intermediate 176: 5-Bromo-N-ethyl-2-methoxynicotinamide

To a solution of 5-bromo-2-methoxynicotinic acid (15 g, 64.6 mmol,commercially available from, for example, Combiblocks) in DCM (100 mL)cooled to 0° C., was added oxalyl dichloride (16.98 mL, 194.0 mmol)followed by the slow addition of DMF (5.01 mL, 64.6 mmol) at 0° C. Thereaction mixture was then stirred for 18 h at rt. A small aliquot of thereaction mixture was taken and quenched with MeOH, the TLC shows thecomplete conversion of SM. The reaction mixture was then concentratedand re-dissolved in DCM (150 mL) and treated with ethanaminehydrochloride (7.91 g, 97 mmol). The reaction mixture was stirred for 3h at rt. After the reaction, water was added and the organics extractedwith ethyl acetate (2×300 mL). The organic layer was separated, driedover Na₂SO₄, filtered and concentrated to obtain the crude product. Thecrude product was purified by column chromatography on a silica gel100-200 column and was eluted with 16% EtOAc/n-hexane. The collectedpure fractions were concentrated under reduced pressure to afford thedesired product 5-bromo-N-ethyl-2-methoxynicotinamide (11 g, 41.0 mmol,64% yield) as an off-white solid.

LCMS (10 min RND-FA-10-MIN): Rt=4.22 min, [MH]⁺=261.

LCMS Conditions: RND-FA-10-MIN:

Column: Acquity BEH C18 (100 mm×2.1 mm, 1.7 μm)

Mobile Phase: A: 0.05% formic acid in ACN; B: 0.05% formic acid in water

Time (min)/% B: 0/97, 0.4/97, 7.5/2, 9.5/2, 9.6/97, 10/97

Column Temp: 35° C., Flow Rate: 0.45 mL/min

Intermediate 177: Butyl 5-(ethylcarbamoyl)-6-methoxynicotinate

To a solution of 5-bromo-N-ethyl-2-methoxynicotinamide (11 g, 41.0 mmol)in DMF (100 mL) was added triethylamine (17.16 mL, 123 mmol), 1-butanol(11.98 mL, 205 mmol) and xantphos (1.662 g, 2.87 mmol) in a steel bomb.The reaction mixture was degassed for 10 min with argon. Thenpalladium(II) acetate (0.921 g, 4.10 mmol) was added and the reactionstirred under a carbon monoxide atmosphere at rt. Then the steel bombwas closed and the reaction was stirred under a carbon monoxideatmosphere (100 psi) at 110° C. for 18 h. After cooling, the reactionmixture was filtered through a Celite pad and washed with ethyl acetate.The filtrate was partitioned between ethyl acetate & cold water. Theorganic phase was washed with saturated brine, dried over Na₂SO₄ andconcentrated under vacuum to afford the crude product. The crude productwas purified by column chromatography on a silica gel 100-200 columnwhich was eluted with 25% EtOAc/n-hexane. The collected pure fractionswere concentrated under reduced pressure to give the desiredproduct—butyl 5-(ethylcarbamoyl)-6-methoxynicotinate (4.4 g, 12.57 mmol,30.6% yield).

LCMS (10 min RND-ABC-10-MIN-V): Rt=4.70 min, [MH]⁺=281.1.

LCMS Conditions: RND-ABC-10-MIN-V

Column: Xbridge C18 (50 mm×4.6 mm, 2.5 μm),

Mobile Phase: A: 5 mM ammonium bicarbonate in water (pH 10); B: ACN

Time (min)/% ACN: 0/5, 0.5/5, 1/15, 6/98, 9/98, 9.5/5, 10/5

Column temp: 35° C., Flow Rate: 1.3 mL

Intermediate 178: 5-(Ethylcarbamoyl)-6-methoxynicotinic acid

To a solution of butyl 5-(ethylcarbamoyl)-6-methoxynicotinate (4.4 g,12.56 mmol) in THF (40 mL), acetonitrile (40 mL) and water (40 mL), wasadded LiOH (0.601 g, 25.1 mmol) at rt. The reaction mixture was stirredat rt for 16 h. After the reaction, the solvent was evaporated invacuum, water was added and the reaction acidified with 1N HCl, (untilpH=2) and then extracted with ethyl acetate (2×200 mL). The organicphase was separated, dried over Na₂SO₄ and concentrated under vacuum toafford the crude product, which was washed with n-pentane (2×10 mL) toafford the pure product—5-(ethylcarbamoyl)-6-methoxynicotinic acid (3 g,12.13 mmol, 97% yield) as a white solid.

LCMS (10 min RND-FA-10-MIN): Rt=2.83 min, [MH]⁺=225.1.

LCMS Conditions: RND-FA-10-MIN:

Column: Acquity BEH C18 (100 mm×2.1 mm, 1.7 μm)

Mobile Phase: A: 0.05% formic acid in ACN; B: 0.05% formic acid in water

Time (min)/% B: 0/97, 0.4/97, 7.5/2, 9.5/2, 9.6/97, 10/97

Column Temp: 35° C., Flow Rate: 0.45 mL/min

Intermediate 179:(+/−)-N³-Ethyl-2-methoxy-N⁵-((trans)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide

To a solution of 5-(ethylcarbamoyl)-6-methoxynicotinic acid (2.8 g,11.24 mmol) in DMF (24 mL) stirred under nitrogen at 0° C., was addedDIPEA (5.89 mL, 33.7 mmol) and HATU (8.55 g, 22.48 mmol) and thereaction stirred for 30 min at rt.(+/−)-(trans)-2-Methylcyclopropanamine (0.959 g, 13.49 mmol,commercially available from, for example, ChemBridge corporation) wasadded to the reaction mixture at 0° C. and the reaction stirred for 16 hat rt. After completion of the reaction, the reaction mixture wasdiluted with water (50 mL) and extracted with EtOAc (2×250 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated to give(+/−)-N³-ethyl-2-methoxy-N⁵-((trans)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide(6 g, 8.22 mmol, 73% yield). This was taken on to the next step withoutpurification.

LCMS (10 min RND-FA-10-MIN): Rt=3.36 min, [MH]⁺=278.1.

LCMS Conditions: RND-FA-10-MIN:

Column: Acquity BEH C18 (100 mm×2.1 mm, 1.7 μm)

Mobile Phase: A: 0.05% formic acid in ACN; B: 0.05% formic acid in water

Time (min)/% B: 0/97, 0.4/97, 7.5/2, 9.5/2, 9.6/97, 10/97

Column Temp: 35° C., Flow Rate: 0.45 mL/min

Intermediate 180:(+/−)-N³-Ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A solution of(+/−)-N³-ethyl-2-methoxy-N⁵-((trans)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide(6 g, 8.22 mmol), TMSCl (3.15 mL, 24.66 mmol) and sodium iodide (3.70 g,24.66 mmol) in acetonitrile (30 mL) was stirred under nitrogen at rt for1 h. After completion of the reaction, the reaction mixture was dilutedwith EtOAc (300 mL) and washed with sodium thiosulphate solution (50mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated to afford the crude product.The crude product was purified by flash chromatography using a 100-200mesh silica gel column eluting with 0-10% MeOH in DCM. The purefractions were collected, concentrated and dried to afford(+/−)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(2 g, 7.22 mmol, 88% yield) as an off white solid.

LCMS (4.5 min RND-FA-4.5-MIN): Rt=1.37 min, [MH]⁺=264.3.

LCMS Conditions: RND-FA-4.5-MIN

Column: Acquity BEH C18 (50 mm×2.1 mm, 1.7 μm)

Mobile Phase: A: 0.05% formic acid in water; B: 0.05% formic acid in ACN

Time (min)/% B: 0/3, 0.4/3, 3.2/98, 3.8/98, 4.2/3, 4.5/3

Column Temp: 35° C., Flow Rate: 0.6 mL/min

Intermediate 181:2-(Benzyloxy)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide

2,4,6-Trichlorophenyl 6-(benzyloxy)-5-(methylcarbamoyl)nicotinate (1022mg, 2.19 mmol), (1S,2S)-2-methylcyclopropanamine hydrochloride (260 mg,2.42 mmol), DMAP (39 mg, 0.319 mmol), triethylamine (0.92 mL, 6.60 mmol)and THF (10 mL) were stirred at 45° C. under N₂. After stirring for 4 h,DMAP (22 mg, 0.18 mmol) and triethylamine (0.3 mL, 2.15 mmol) were addedand the reaction stirred overnight. The suspension was then partitionedbetween EtOAc (20 mL) and sodium bicarbonate solution. (20 mL),extracted with EtOAc (20 mL), dried over a hydrophobic frit andconcentrated to give the crude product (1.57 g) as a cream solid. Thiswas purified by chromatography on SiO₂ (Biotage SNAP 100 g cartridge,eluting with 0-100% EtOAc/cyclohexane). The desired fractions wereconcentrated to give2-(benzyloxy)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide(321 mg, 0.85 mmol, 39% yield).

LCMS (2 min Formic): Rt=0.98 min, [MH]⁺=340.2.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.67 (d, J=2.4 Hz, 1H) 8.53 (br. d,J=3.9 Hz, 1H) 8.46 (d, J=2.4 Hz, 1H) 8.24-8.32 (m, 1H) 7.44-7.50 (m, 2H)7.38 (t, J=7.2 Hz, 2H) 7.28-7.34 (m, 1H) 5.55 (s, 2H) 2.80 (d, J=4.6 Hz,3H) 2.51-2.57 (m, 1H) 1.06 (d, J=6.1 Hz, 3H) 0.87-0.98 (m, 1H) 0.74 (dt,J=8.6, 4.6 Hz, 1H) 0.48 (dt, J=7.3, 5.5 Hz, 1H)

Intermediate 182:N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2-(Benzyloxy)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)pyridine-3,5-dicarboxamide(320 mg, 0.94 mmol) was stirred in TFA (3 mL, 38.9 mmol) at 90° C. After1 h the sample was concentrated to give the crude product (633 mg) as ared oil. This was purified by chromatography on SiO₂ (Biotage SNAP 50 gcartridge, eluting with 0-50% (25% EtOH in EtOAc)/EtOAc). The desiredfractions were concentrated and dried in vacuo to giveN³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(297 mg, 0.94 mmol, 100% yield) as a cream solid.

LCMS (2 min Formic): Rt=0.54 min, [MH]⁺=250.1.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.77 (br. d, J=5.9 Hz, 1H) 9.37-9.45(m, 1H) 8.76 (d, J=2.9 Hz, 1H) 8.42 (d, J=3.9 Hz, 1H) 8.18 (dd, J=6.8,2.7 Hz, 1H) 2.83 (d, J=4.6 Hz, 3H) 2.47-2.53 (obs, 1H) 1.04 (d, J=6.1Hz, 3H) 0.84-0.95 (m, 1H) 0.71 (dt, J=8.9, 4.5 Hz, 1H) 0.46 (dt, J=7.3,5.5 Hz, 1H)

Intermediate 183: (S*)-Butyl1-(1-(3-methoxyphenyl)ethyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Butyl 5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (200mg, 0.79 mmol) and potassium carbonate (219 mg, 1.59 mmol) were stirredin DMF (4.0 mL) under nitrogen at rt, before the addition of1-(1-bromoethyl)-3-methoxybenzene (286 mg, 1.33 mmol). The reaction wasstirred at rt for 24 h. The reaction mixture was poured onto 3:1brine:water (50 mL) and the aqueous layer was extracted with ethylacetate (3×20 mL). The combined organics were washed with brine, driedthrough a hydrophobic frit and evaporated in vacuo to yield the crudeproduct as an orange solvate in DMF. The residue was loaded indichloromethane onto a 25 g SNAP cartridge and purified via Biotage SP4flash chromatography, eluting from 15-75% ethyl acetate/cyclohexane. Therelevant fractions were combined and evaporated in vacuo to yield thedesired product (+/−)-butyl1-(1-(3-methoxyphenyl)ethyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(268 mg, 0.66 mmol, 83% yield) as an orange gum.

The racemate (257 mg) was dissolved in EtOH (˜8-10 mL) with heat.Injection: 0.3 mL manual injections were made via a Rheodyne valve ontothe column (10% EtOH (with 0.2% v/v isopropylamine)/heptane (with 0.2%v/v isopropylamine), flow rate=42.5 mL/min (pressure: 83 bar),detection: UV Diode Array at 280 nm (Band width 1 40 nm, reference 400nm, bandwidth 100 nm), Column Chiralpak AD-H (250×30 mm, 5 μm).Fractions from 19-21 min were bulked and labelled peak 1. Fractions from22-24 min were bulked and labelled peak 2. The bulked fractions wereconcentrated in vacuo, then taken up in EtOH and transferred to weighedflasks which were blown down to dyness under a stream of nitrogen gas.

The fractions corresponding to peak 1 were collected to affordintermediate 183 (102 mg, 0.25 mmol, 32%)

LCMS (2 min formic): Rt=1.22 min, [MH]⁺=387.2.

The fractions corresponding to peak 2 were also collected to afford theundesired enantiomer (115 mg, 0.28 mmol, 36% yield)

Intermediate 184:(S*)-1-(1-(3-Methoxyphenyl)ethyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

(S*)-Butyl1-(1-(3-methoxyphenyl)ethyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(100 mg, 0.26 mmol) was suspended in 1,4-dioxane (863 μL). Water (863μL) was added, followed by lithium hydroxide (17 mg, 0.71 mmol) and thereaction mixture was stirred at rt for 1.5 h. The reaction mixture wasthen neutralized with 2M HCl and evaporated in vacuo to yield(S*)-1-(1-(3-methoxyphenyl)ethyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (121 mg, 0.22 mmol, 85% yield) as a white solid. The purity wasestimated at 60% based on the projected quantity of NaCl in residue.

LCMS (2 min formic): Rt=0.87 min, [MH]⁺=331.1.

Intermediate 185: Butyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Butyl 5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2 g,7.93 mmol), 1-(bromomethyl)-3-methoxybenzene (1.6 mL, 11.43 mmol),potassium carbonate (2.2 g, 15.92 mmol) and DMF (10 mL) were stirred at90° C. for 1 h. The reaction mixture was then washed with LiCl (20 mL)and partitioned between EtOAc (40 mL) and water (40 mL). The aqueousphase was extracted with EtOAc (2×40 mL) and the combined organics driedover a hydrophobic frit and concentrated to give the crude product(˜2.49 g) as an orange solid. This was purified by chromatography onSiO₂ (Biotage SNAP 100 g cartridge, eluting with 10-75%EtOAc/cyclohexane). The appropriate fractions were concentrated to givebutyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(2.01 g, 4.86 mmol, 61% yield) as an off white solid.

LCMS (2 min Formic): Rt=1.16 min, [MH]⁺=373.2.

Intermediate 186: Butyl1-(3-hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Butyl1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(500 mg, 1.34 mmol) in DCM (8 mL) was cooled to 0° C. under N₂ and BBr₃(1M in DCM, 6.71 mL, 6.71 mmol) was added dropwise. After 10 min, thereaction was quenched with water (40 mL) and extracted with DCM (3×20mL). The organic extract was then washed with sat. NaHCO₃ solution,dried (Na₂SO₄) and concentrated to give butyl1-(3-hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(328 mg, 0.82 mmol, 61% yield) as an off-white solid.

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=359.2.

Intermediate 187: (S)-Butyl1-(3-(2-hydroxypropoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

A mixture of butyl1-(3-hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(100 mg, 0.28 mmol), (S)-2-methyloxirane (0.098 mL, 1.40 mmol,commercially available from, for example, Alfa Aesar) and Et₃N (0.078mL, 0.56 mmol) were dissolved in DMF (1 mL) and the reaction mixture washeated at 150° C. for 30 min in a 2 mL microwave vial.

Separately, a mixture of butyl1-(3-hydroxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(35 mg, 0.10 mmol), (S)-2-methyloxirane (0.034 mL, 0.49 mmol) and Et₃N(0.027 mL, 0.20 mmol) were dissolved in DMF (0.5 mL) and the reactionmixture was heated at 150° C. for 30 min in a 2 mL microwave vial.

Both reaction mixtures were combined and partitioned between ethylacetate and water. The organic layer was separated and the aqueous layerfurther extracted with ethyl acetate (2×20 mL). The combined organiclayers were dried (Na₂SO₄) and concentrated to give the crude product(148 mg) as a pale yellow oil. This was purified by chromatography onSiO₂ (Biotage SNAP 10 g cartridge, eluting with 0-100%EtOAc/cyclohexane). The appropriate fractions were concentrated to give(S)-butyl1-(3-(2-hydroxypropoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(115 mg, 0.25 mmol, 89% yield) as a colourless oil.

¹H NMR (400 MHz, MeOH-d₄) δ ppm 8.84 (d, J=2.4 Hz, 1H) 8.64 (d, J=2.7Hz, 1H) 7.26 (t, J=7.9 Hz, 1H) 6.86-6.97 (m, 3H) 5.27 (s, 2H) 4.28 (t,J=6.6 Hz, 2H) 4.01-4.13 (m, 1H) 3.79-3.89 (m, 2H) 2.93 (s, 3H) 1.66-1.77(m, 2H) 1.37-1.50 (m, 2H) 1.24 (d, J=6.6 Hz, 3H) 0.96 (t, J=7.5 Hz, 3H).Exchangeable protons not observed.

Intermediate 188:(S)-1-(3-(2-Hydroxypropoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

(S)-Butyl1-(3-(2-hydroxypropoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(115 mg, 0.28 mmol) was dissolved in 1,4-dioxane (3 mL). Water (3 mL)was added, followed by LiOH (14 mg, 0.59 mmol) and the reaction mixturestirred at rt for 2 h. The dioxane was removed in vacuo and acetic acid(0.032 mL, 0.55 mmol) was added. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was separated and theaqueous layer extracted with further ethyl acetate (4×20 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated to give(S)-1-(3-(2-hydroxypropoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (106 mg, 0.27 mmol, 96% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=361.2.

Intermediate 189:1-((1-(tert-Butoxycarbonyl)indolin-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

tert-Butyl4-((5-(butoxycarbonyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)indoline-1-carboxylate(380 mg, 0.79 mmol) was taken up in THF (3 mL) and water (3 mL). LiOH(37.6 mg, 1.57 mmol) was added to the solution and the reaction stirredovernight at rt. HCl (2M, aq.) was added to acidify the solution to ˜pH5. The reaction mixture was then extracted using DCM. The organic layerswere combined, passed through a hydrophobic frit and concentrated invacuo to give1-((1-(tert-butoxycarbonyl)indolin-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (312 mg, 0.73 mmol, 93% yield).

LCMS (2 min Formic): Rt=1.07 min, [MH]⁺=428

Intermediate 190:N⁵-Cyclopropyl-N³-methyl-1-((2-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a stirred solution ofN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (60mg, 0.26 mmol) and potassium carbonate (106 mg, 0.77 mmol) in DMF (2.3mL) under nitrogen at rt, was added4-(bromomethyl)-2-methyl-1-tosyl-1H-indole (322 mg, 0.51 mmol, 60% wt)as a solution in DMF (2.3 mL) and the reaction stirred for 3 h. Afurther portion of potassium carbonate (70.5 mg, 0.51 mmol) was added.The reaction was stirred for 19 h. Further portions ofN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (20mg, 0.09 mmol) and potassium carbonate (35.3 mg, 0.26 mmol) were added.After 22.5 h a further portion ofN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (30mg, 0.13 mmol) was added. After 24 h the reaction mixture was pouredonto sat. aqueous LiCl (25 mL) and extracted with ethyl acetate (20 mL,then 2×10 mL). The combined ethyl acetate portions were washed withbrine, dried through a hydrophobic frit and evaporated in vacuo to yieldthe crude product (379 mg). The sample was loaded in dichloromethaneonto a 50 g SNAP cartridge and purified via Biotage SP4 flashchromatography, eluting with 0-50% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo. The residue was sonicated with diethyl ether andevaporated in vacuo again to yieldN⁵-cyclopropyl-N³-methyl-1-((2-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(78 mg, 0.14 mmol, 30% yield) as a white solid.

LCMS (2 min formic): Rt=1.17 min, [MH]⁺=533.4.

Intermediate 191:(+/−)-N³-Ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide

A solution of(+/−)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(100 mg, 0.36 mmol), 4-(bromomethyl)-1-tosyl-1H-indole (201 mg, 0.54mmol) and K₂CO₃ (100 mg, 0.72 mmol) in DMF (2 mL) was stirred undernitrogen at 90° C. for 2 h. After 16 h, the reaction mixture was cooledto rt, diluted with water (50 mL) and extracted with EtOAc (2×50 mL).The combined organic layer was dried over anhydrous Na₂SO₄, filtered andthe filtrate was concentrated to afford the crude product. This waspurified by flash chromatography using a 100-200 mesh silica gel columneluting with 0-5% MeOH in DCM. The pure fractions were collected,concentrated and dried to afford(+/−)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(150 mg, 0.24 mmol, 67% yield) as a yellow solid.

LCMS (5.5 min RND-FA-5-5-MIN-50): Rt=3.10 min, [MH]⁺=547.3.

LCMS Conditions: RND-FA-5-5-MIN-50

Column: Acquity BEH C18 (50 mm×2.1 mm, 1.7 μm)

Mobile Phase: B: 0.05% formic acid in ACN; A: 0.05% formic acid in water

Time (min)/% A: 0/97, 0.4/97, 4.0/2, 4.5/2, 5/97, 5.5/97

Column Temp: 35° C., Flow Rate: 0.45 mL/min

Intermediate 192: (+/−)-tert-Butyl4-((3-(ethylcarbamoyl)-5-(((trans)-2-methylcyclopropyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)indoline-1-carboxylate

To a solution of(+/−)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(150 mg, 0.541 mmol), triphenylphosphine (426 mg, 1.624 mmol) and DIAD(0.316 mL, 1.624 mmol) in toluene (5 mL) stirred under nitrogen at rt,was added tert-butyl 4-(hydroxymethyl)indoline-1-carboxylate (215 mg,0.812 mmol). The reaction mixture was stirred at rt for 16 h. Thereaction mixture was quenched with water and extracted with DCM (2×100mL). The organic phase was washed with saturated brine (25 mL), driedover sodium sulphate, filtered and evaporated in vacuo to give(+/−)-tert-butyl4-((3-(ethylcarbamoyl)-5-(((trans)-2-methylcyclopropyl)carbamoyl)-2-oxopyridin-1(2H)-yl)methyl)indoline-1-carboxylate(400 mg, 0.259 mmol, 47.8% yield) as a brown solid. The compound wasused crude in the next reaction

LCMS (5.5 min RND-FA-5-5-MIN-50): Rt=3.06 min, [MH]⁺=395.2.

LCMS Conditions: RND-FA-5-5-MIN-50

Column: Acquity BEH C18 (50 mm×2.1 mm, 1.7 μm)

Mobile Phase: B: 0.05% formic acid in ACN; A: 0.05% formic acid in water

Time (min)/% A: 0/97, 0.4/97, 4.0/2, 4.5/2, 5/97, 5.5/97

Column Temp: 35° C., Flow Rate: 0.45 mL/min

Intermediate 193:(+/−)-N³-Ethyl-1-(3-methoxybenzyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A solution of(+/−)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(300 mg, 1.08 mmol), 1-(bromomethyl)-3-methoxybenzene (326 mg, 1.62mmol) and K₂CO₃ (299 mg, 2.17 mmol) in DMF (2 mL) was stirred undernitrogen at 60° C. for 1 h. The reaction mixture was then diluted withEtOAc (100 mL) and washed with water (50 mL). The combined organic layerwas dried over anhydrous Na₂SO₄, filtered and the filtrate wasconcentrated to afford the crude product. This was purified by flashchromatography using a 100-200 mesh silica gel column and eluting with0-10% MeOH in DCM. The pure fractions were collected, concentrated anddried to obtain(+/−)-N³-ethyl-1-(3-methoxybenzyl)-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(320 mg, 0.69 mmol, 64% yield) as an off white solid.

LCMS (5.5 min RND-FA-5-5-MIN-50): Rt=2.54 min, [MH]⁺=384.1.

LCMS Conditions: RND-FA-5-5-MIN-50

Column: Acquity BEH C18 (50 mm×2.1 mm, 1.7 μm)

Mobile Phase: B: 0.05% formic acid in ACN; A: 0.05% formic acid in water

Time (min)/% A: 0/97, 0.4/97, 4.0/2, 4.5/2, 5/97, 5.5/97

Column Temp: 35° C., Flow Rate: 0.45 mL/min

Intermediate 194:(+/−)-N³-Ethyl-1-(3-hydroxybenzyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of(+/−)-N³-ethyl-1-(3-methoxybenzyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(320 mg, 0.69 mmol) in DCM (2 mL) stirred under nitrogen at −10° C., wasadded BBr₃ (1.385 mL, 1.39 mmol, 1M in DCM). The reaction mixture wasstirred at 0° C. for 30 min. The reaction mixture was then quenched withwater and extracted with DCM (2×100 mL). The organic phase was washedwith saturated brine (25 mL), dried over sodium sulphate, filtered andevaporated in vacuo to afford the crude product. This was purified byflash chromatography, using a 100-200 mesh silica gel column and elutingwith 0-10% MeOH in DCM. The pure fractions were collected, concentratedand dried to obtain(+/−)-N³-ethyl-1-(3-hydroxybenzyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(150 mg, 0.40 mmol, 57% yield) as an off white solid.

LCMS (5.5 min RND-FA-5-5-MIN-50): Rt=2.19 min, [MH]⁺=370.1.

LCMS Conditions: RND-FA-5-5-MIN-50

Column: Acquity BEH C18 (50 mm×2.1 mm, 1.7 μm)

Mobile Phase: B: 0.05% formic acid in ACN; A: 0.05% formic acid in water

Time (min)/% A: 0/97, 0.4/97, 4.0/2, 4.5/2, 5/97, 5.5/97

Column Temp: 35° C., Flow Rate: 0.45 mL/min

Intermediate 195:(+/−)-1-(3-(2-Hydroxyethoxy)benzyl)-N⁵-((trans)-2-hydroxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(3-(2-Hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (120 mg, 0.35 mmol) was taken up in DMF (5 mL) and HATU (145 mg,0.38 mmol) followed by DIPEA (0.121 mL, 0.69 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then(+/−)-((trans)-2-aminocyclopropyl)methanol (30.2 mg, 0.35 mmol) wasadded and the reaction allowed to stir overnight. The reaction mixturewas concentrated in vacuo and purified by MDAP (High pH). Theappropriate fractions were combined and concentrated in vacuo to give(+/−)-1-(3-(2-hydroxyethoxy)benzyl)-N⁵-((trans)-2-(hydroxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(51 mg, 0.12 mmol, 35% yield) as an orange solid.

LCMS (2 min Formic): Rt=0.62 min, [MH]+=416

Intermediate 196:(+/−)-N⁵-((trans)-2-Ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(3-(2-Hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (150 mg, 0.43 mmol) was taken up in DMF (4 mL) and HATU (181 mg,0.48 mmol) followed by DIPEA (0.151 mL, 0.87 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then(+/−)-(trans)-2-ethoxycyclopropanamine, hydrochloride (65.6 mg, 0.48mmol) was added and the reaction allowed to stir overnight. The reactionmixture was purified by MDAP (High pH). The appropriate fractions werecombined and concentrated in vacuo to give(+/−)-N⁵-((trans)-2-ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(130 mg, 0.30 mmol, 70% yield) as a white solid.

LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=430

Intermediate 197:N³-Methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1-(3-(2-oxoethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide

Dess-Martin Periodinane (237 mg, 0.56 mmol) was added to a solution of1-(3-(2-hydroxyethyl)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(165 mg, 0.43 mmol) in DCM (4 mL) at 0° C. The reaction mixture wasallowed to warm to rt and stirred overnight. The reaction was quenchedwith sat. sodium bicarbonate solution and extracted with DCM. Theorganic layer was passed through a hydrophobic frit and concentrated invacuo to give crudeN³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1-(3-(2-oxoethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide(150 mg, 0.20 mmol, 46% yield) as a white solid.

LCMS (2 min Formic): Rt=0.78 min, [MH]⁺=382

Intermediate 198:N⁵-Cyclopropyl-N³-methyl-2-oxo-1-(3-(2-oxoethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide

Dess-Martin periodinane (149 mg, 0.35 mmol) was added to a solution ofN⁵-cyclopropyl-1-(3-(2-hydroxyethyl)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(100 mg, 0.27 mmol) in DCM (2.5 mL) at 0° C. The reaction mixture wasallowed to warm to rt and stirred for 48 h. The reaction was quenchedwith water and extracted with DCM. The organic layer was passed througha hydrophobic frit and concentrated in vacuo to giveN⁵-cyclopropyl-N³-methyl-2-oxo-1-(3-(2-oxoethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide(100 mg, 0.27 mmol, 101% yield) as a white solid, which was used crudein the next step.

LCMS (2 min Formic): Rt=0.70 min, [MH]+=368

Intermediate 199: (+/−)-tert-Butyl4-((5-(((trans)-2-ethylcycloropyl)carbamoyl-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)indoline-1-carboxylate

1-((1-(tert-Butoxycarbonyl)indolin-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (70 mg, 0.16 mmol) was taken up in DMF (1.5 mL) and HATU (68.5 mg,0.18 mmol) followed by DIPEA (0.086 mL, 0.491 mmol) was added. Thereaction mixture was allowed to stir for 5 min, then(+/−)-trans-2-ethylcyclopropanamine (15.34 mg, 0.18 mmol, commerciallyavailable from, for example, Enamine) was added and the reaction allowedto stir overnight. The reaction mixture was concentrated in vacuo andpartitioned between EtOAc (15 mL) and citric acid solution (aq, 15 mL,10% w/v). The EtOAc layer was then washed with sat. NaHCO₃ (aq), waterand brine. The EtOAc layer was concentrated in vacuo, loaded in DCM andpurified by Biotage Isolera flash chromatography using a SNAP 10 gsilica cartridge and eluting with a gradient of 0-70% EtOAc/cyclohexane.The appropriate fractions were combined and concentrated in vacuo togive (+/−)-tert-butyl4-((5-(((trans)-2-ethylcyclopropyl)carbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)indoline-1-carboxylate(54 mg, 0.11 mmol, 67% yield) as a colourless residue.

LCMS (2 min Formic): Rt=1.21 min, [MH]⁺=495

Intermediate 200: tert-Butyl(trans-4-(2-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)ethyl)cyclohexyl)carbamate

To a solution of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(50.4 mg, 0.18 mmol), HATU (87.3 mg, 0.23 mmol) and tert-butyl(trans-4-(2-aminoethyl)cyclohexyl)carbamate (52.3 mg, 0.22 mmol;commercially available from Matrix Scientific) in DMF (1 mL) was addedN,N-diisopropylethylamine (0.061 mL, 0.35 mmol). The reaction mixturewas stirred at rt for 1 h before being concentrated under a stream ofnitrogen. The residue was made up to 2 mL with a 1:1 mixture ofdimethylsulphoxide/methanol and directly purified by MDAP (2×1 mLinjection; high pH). The required fractions from both injections werecombined and concentrated in vacuo before being dissolved in a 1:1mixture of dichloromethane/methanol (10 mL), concentrated under a streamof nitrogen and dried in vacuo to give a white solid; tert-butyl(trans-4-(2-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)ethyl)cyclohexyl)carbamate(78.4 mg, 0.15 mmol, 87% yield).

LCMS (2 min formic) Rt=1.16 min, m/z=511 for [MH]⁺

Intermediate 201: tert-Butyl(cis-4-(2-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)ethyl)cyclohexyl)carbamate

To a solution of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(51 mg, 0.18 mmol), HATU (89.2 mg, 0.24 mmol) and tert-butylcis-4-(2-aminoethyl)cyclohexyl)carbamate (52.2 mg, 0.22 mmol,commercially available from, for example, Matrix Scientific) in DMF (1mL) was added N,N-diisopropylethylamine (0.062 mL, 0.36 mmol). Thereaction mixture was stirred at rt for 1 h before being concentratedunder a stream of nitrogen. The residue was made up to 1 mL withdimethylsulphoxide and directly purified by MDAP (1 mL injection; highpH). The required fractions were combined and concentrated in vacuobefore being dissolved in a 1:1 mixture of dichloromethane/methanol (10mL), concentrated under a stream of nitrogen and dried in vacuo to givea white solid; tert-butyl(cis-4-(2-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)ethyl)cyclohexyl)carbamate(74.4 mg, 0.15 mmol, 82% yield).

LCMS (2 min formic) Rt=1.16 min, m/z=511 for [MH]⁺

Intermediate 202:N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1-((1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide

To a mixture of (1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)methanol (143.5mg, 0.38 mmol) andN³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(77.1 mg, 0.31 mmol) in toluene (1.5 mL) in a microwave vial was added2-(tributylphosphoranylidene)acetonitrile (0.162 mL, 0.62 mmol). Thevial was sealed and the mixture heated in a microwave reactor at 100° C.for a total of 40 min. The reaction mixture was evaporated under astream of nitrogen to give a viscous black oil which was redissolved indichloromethane (approx. 3 mL), directly applied to the top of a 25 gSNAP cartridge and purified by SP4 flash column chromatography. Thecolumn was eluted with a gradient of 0-40% ethyl acetate:ethanol (3:1)in cyclohexane. The required fractions were combined and evaporated invacuo to give an orange gum which was redissolved in DMSO (approx. 1 mL)and further purified by MDAP (1 mL injection, high pH). The remainingsample in the injection vial (approx. 0.5 mL) was made up to 1 mL inDMSO and was also purified by MDAP (1 mL injection, high pH). Therequired fractions from both injections were combined and evaporated invacuo to give a colourless gum;N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1-((1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(36.5 mg, 0.07 mmol, 22% yield).

LCMS (2 min high pH) Rt=1.09 min, m/z=534 for [MH]⁺

¹H NMR (400 MHz, CDCl₃) δ ppm 9.48 (br. d, J=3.4 Hz, 1H) 8.84 (br. s.,1H) 8.64 (d, J=2.0 Hz, 1H) 8.36 (d, J=5.6 Hz, 1H) 7.74-7.92 (m, 3H) 7.63(d, J=3.4 Hz, 1H) 7.28 (d, J=8.3 Hz, 2H) 6.99-7.19 (m, 1H) 6.89 (d,J=3.2 Hz, 1H) 5.54 (s, 2H) 2.90 (d, J=4.2 Hz, 3H) 2.48-2.57 (m, 1H) 2.37(s, 3H) 1.10 (d, J=5.9 Hz, 3H) 0.86-1.00 (m, 1H) 0.68-0.79 (m, 1H)0.54-0.65 (m, 1H)

Intermediate 203: Methyl3-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate

N⁵-Cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(42.1 mg, 0.18 mmol), methyl 3-(bromomethyl)benzoate (45.9 mg, 0.20mmol; commercially available from, for example, Alfa Aesar) andpotassium carbonate (52.1 mg, 0.38 mmol) were stirred in anhydrous DMF(1 mL) at rt under nitrogen for 2.5 h. The reaction mixture waspartitioned between water (5 mL) and ethyl acetate (5 mL). The aqueousphase was extracted with further ethyl acetate (3×5 mL) and the combinedorganic phases were filtered through a cartridge fitted with ahydrophobic frit. The solvent was evaporated under a stream of nitrogenand the residue was dissolved in a 1:1 mixture ofdichloromethane/methanol (6 mL), concentrated under a stream of nitrogenand dried in vacuo to give a white solid; methyl3-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate(65.5 mg, 0.17 mmol, 95% yield).

LCMS (2 min formic) Rt=0.82 min, m/z=384 for [MH]⁺

Intermediate 204: tert-Butyl3-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

To a suspension ofN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (53mg, 0.23 mmol) and tert-butyl3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (69.2 mg, 0.28mmol) in toluene (1.5 mL) in a microwave vial, was added2-(tributylphosphoranylidene)acetonitrile (0.186 mL, 0.71 mmol;commercially available from, for example, TCI). The vial was sealed andheated in a microwave reactor at 80° C. for a total of 60 min. Thereaction mixture was transferred to a vial using dichloromethane (2 mL)and concentrated under a stream of nitrogen to give a dark brown oil.This was made up to 3 mL with a 1:1 mixture ofdimethylsulphoxide/methanol (3 mL) and directly purified by MDAP (3×1 mLinjection, high pH). The required fractions were combined andconcentrated in vacuo before being dissolved in a 1:1 mixture ofdichloromethane/methanol (10 mL), concentrated under a stream ofnitrogen and dried in vacuo to give a yellow solid; tert-butyl3-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(44.3 mg, 0.10 mmol, 42% yield).

LCMS (2 min formic) Rt=0.90 min, m/z=466 for [MH]⁺

Intermediate 205:1-((1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a suspension ofN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (57mg, 0.24 mmol) and(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)methanol (85.1mg, 0.28 mmol) in toluene (1.5 mL) in a microwave vial, was added2-(tributylphosphoranylidene)acetonitrile (0.200 mL, 0.76 mmol;commercially available from, for example, TCI). The vial was sealed andheated in a microwave reactor at 80° C. for 30 min and then for 30 minat 120° C. in a microwave reactor. The reaction mixture was transferredto a vial using dichloromethane (1 mL) and was concentrated under astream of nitrogen to give a dark brown oil. This was made up to 3 mLwith a 1:1 mixture of dimethylsulphoxide/methanol and directly purifiedby MDAP (1×3 mL injection: high pH). The required fractions wereconcentrated under a stream of nitrogen before being dissolved in a 1:1mixture of dichloromethane/methanol (2×4 mL), combined, concentratedunder a stream of nitrogen and dried in vacuo to give a pale brownsolid;1-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(34.3 mg, 0.07 mmol, 27% yield).

LCMS (2 min high pH) Rt=1.37 min, m/z=521 for [M−H]⁻

Intermediate 206:(+/−)-1-((1H-Indol-4-yl)methyl)-N⁵-((trans)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-((1H-Indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (400 mg, 1.230 mmol) was taken up in DMF (5 mL). DIPEA (0.644 mL,3.69 mmol) then HATU (701 mg, 1.84 mmol) were added and the reactionstirred at rt for 10 min.(+/−)-(trans)-2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)cyclopropanamine(318 mg, 1.48 mmol) was added and the reaction stirred at rt overnight.The reaction was concentrated in vacuo and the residue was partitionedbetween EtOAc and sat. NaHCO₃ (25 mL each). The aqueous layer wasre-extracted with EtOAc (25 mL) and the combined organics were washedwith brine, dried with Na₂SO₄, filtered through a hydrophobic frit andconcentrated in vacuo to yield an orange oil. The crude product wasapplied to a 25 g ULTRA SNAP cartridge in the minimum of DCM andpurified by flash chromatography, eluting with 10-60% (3:1EtOAc:EtOH)/cyclohexane. The appropriate fractions were concentrated togive(+/−)-1-((1H-indol-4-yl)methyl)-N⁵-((trans)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(203.1 mg, 0.35 mmol, 28% yield) as a cream solid.

LCMS (2 min High pH): Rt=1.33 min, [MH]⁺=523.4.

Intermediate 207: (+/−)-tert-Butyl(2-((2-((trans)-2-(1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclopropyl)ethyl(methyl)amino)ethyl)carbamate

(+/−)-1-((1H-Indol-4-yl)methyl)-N⁵-((trans)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(50 mg, 0.12 mmol) was suspended in DCM (5 mL) under nitrogen. Et₃N(0.034 mL, 0.25 mmol) then mesyl-Cl (10.49 μL, 0.14 mmol) were added andthe reaction stirred at rt. After 45 min the reaction was diluted withDCM (5 mL) then washed with water (10 mL) then eluted through ahydrophobic frit and concentrated in vacuo to give a red oil. The oilwas taken up in acetonitrile (5 mL). Et₃N (0.034 mL, 0.245 mmol) thentert-butyl (2-(methylamino)ethyl)carbamate (32.0 mg, 0.18 mmol) wereadded and the reaction heated to 80° C. overnight. An additional portionof Et₃N (0.034 mL, 0.245 mmol) and tert-butyl(2-(methylamino)ethyl)carbamate (32.0 mg, 0.18 mmol) were added andstirring at 80° C. continued over the weekend. The reaction had boileddry so the residue was applied to a 10 g ULTRA SNAP cartridge in theminimum of DCM and purified by flash chromatography, eluting with 1-10%(2M NH₃ in methanol) in DCM. The appropriate fractions were concentratedin vacuo to give (+/−)-tert-butyl(2-((2-((1S,2S)-2-(1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclopropyl)ethyl)(methyl)amino)ethyl)carbamate(44 mg, 0.07 mmol, 54% yield) as a brown oil.

LCMS (2 min High pH): Rt=1.03 min, [MH]⁺=565.5.

EXAMPLES Example 1:1-Benzyl-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-Benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(5.5 g, 19.21 mmol) was suspended in DCM (100 mL) and Et₃N (3.21 mL,23.05 mmol), HATU (9.50 g, 24.98 mmol) and cyclopropylamine (1.625 mL,23.05 mmol) were added, then the mixture was stirred for 2 h at rt. Themixture was washed with water (100 mL), 0.5 M HCl (100 mL) and saturatedsodium bicarbonate solution (100 mL) and the organic layer was dried andevaporated in vacuo to give a pale yellow solid. The solid was suspendedin ether (20 mL) and sonicated, then filtered and the solid dried in thevacuum oven to give1-benzyl-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(5.25 g, 16.14 mmol, 84% yield) as a colourless solid.

The product was combined with another batch, prepared by a similarmethod (2.4 g), the combined material was dissolved by refluxing inethanol (200 mL) for 20 min, then Silicycle thiourea palladiumscavenging resin (10 g) was added and the mixture heated for a further30 min. The mixture was filtered into a Buchner flask and allowed tocool to rt over 1 h, then cooled in an ice bath for 1 h and theresulting solid collected by filtration and dried in the vacuum oven togive1-benzyl-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(6.76 g, 20.78 mmol) as a colourless solid.

LCMS (2 min high pH): Rt=0.84 min, [MH]⁺=326.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.35 (d, J=4.9 Hz, 1H) 8.80 (d, J=2.7Hz, 1H) 8.72 (d, J=2.7 Hz, 1H) 8.54 (d, J=3.9 Hz, 1H) 7.25-7.42 (m, 5H)5.29 (s, 2H) 2.75-2.89 (m, 4H) 0.65-0.72 (m, 2H) 0.53-0.59 (m, 2H).

Example 2:1-Benzyl-N5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2,4,6-Trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(401 mg, 0.861 mmol), cyclobutanamine (0.15 mL, 1.757 mmol),N,N-dimethylpyridin-4-amine (23 mg, 0.188 mmol), triethylamine (0.48 mL,3.44 mmol) and THF (8 mL) were stirred at 45° C. under N₂ for 3 h. Thereaction mixture was concentrated to give 600 mg of an off white solidwhich was purified by chromatography on SiO₂ (Biotage SNAP 50 gcartridge, eluting with 0-100% ethylacetate/cyclohexane). The desiredfractions were concentrated to give1-benzyl-N5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(295 mg, 0.782 mmol, 91% yield) as an off white solid

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=340.

Example 3:N5-Cyclopropyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide

THF (1.5 mL) was added to a sealed microwave vial containing5-bromo-N-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3-carboxamide(100 mg, 0.298 mmol), dicobalt octacarbonyl (28.3 mg, 0.075 mmol), DMAP(109 mg, 0.895 mmol), xantphos (10.36 mg, 0.018 mmol) and palladium (II)acetate (3.35 mg, 0.015 mmol) and flushed with N2. Cyclopropylamine(0.042 mL, 0.597 mmol) was added and the reaction mixture heated to 80°C. by microwave irradiation for 30 min. The reaction mixture waspartitioned between EtOAc and water. The aqueous layer was removed, theorganic layer washed (1× water, 2×2 M aq. HCl, 1× brine), dried overMgSO₄ and evaporated in vacuo to a yellow residue. The residue wasdissolved in DCM, loaded onto a 10 g Biotage silica SNAP column andeluted with cyclohexane:EtOAc (50-100%). The product containingfractions were evaporated in vacuo to a brown gum. The gum was stirredwith TBME and evaporated in vacuo to give the product (41 mg) as a whitesolid.

LCMS (2 min TFA): Rt=0.85 min, [MH]⁺=340.1.

Example 4:rac-N5-Cyclopropyl-N3-methyl-2-oxo-1-(1-phenylpropyl)-1,2-dihydropyridine-3,5-dicarboxamide

To a suspension ofN5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (40mg, 0.170 mmol), (1-bromopropyl)benzene (41 mg, 0.206 mmol) in DMF (1mL), was added K₂CO₃ (29 mg, 0.210 mmol) and the reaction stirred undernitrogen at rt for 2 h. The reaction mixture was purified by MDAP(Formic) and the fractions containing desired product were concentratedto giverac-N5-cyclopropyl-N3-methyl-2-oxo-1-(1-phenylpropyl)-1,2-dihydropyridine-3,5-dicarboxamide(25 mg, 0.064 mmol, 37.4% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.97 min, [MH]⁺=354.

Example 5:N5-Cyclobutyl-1-((2,3-dihydrobenzo[b][1.4]dioxin-5-yl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

N5-Cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (50mg, 0.201 mmol), (2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanol (50.0 mg,0.301 mmol) and 2-(tributylphosphoranylidene)acetonitrile (0.166 mL,0.632 mmol) were combined in toluene (1.5 mL) and the reaction mixtureheated in a 5 mL microwave vial on a Biotage Initiator microwave at 120°C. for 30 min. The reaction mixture was poured onto water (20 mL), andextracted with ethyl acetate (3×10 mL). The combined organic portionswere evaporated in vacuo to yield the crude product as a brown oil. Theproduct was loaded in dichloromethane onto a 25 g SNAP silica cartridgeand purified via Biotage SP4 flash chromatography, eluting from 50-100%ethyl acetate/cyclohexane. The relevant fractions were combined andevaporated in vacuo—yielding 76 mg of product. The sample was dissolvedin MeOH/DMSO (1 mL, 1:1) and purified by MDAP (Formic). The solvent wasevaporated in vacuo to give the requiredproduct—N5-cyclobutyl-1-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(40 mg, 0.096 mmol, 47.7% yield).

LCMS (2 min Formic): Rt=0.95 min, [MH]⁺=398.1.

Example 6:N5-Cyclobutyl-N3-methyl-1-(3-(methylamino)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

N5-Cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (25mg, 0.100 mmol), (3-(methylamino)phenyl)methanol (20.64 mg, 0.150 mmol)and 2-(tributylphosphoranylidene)acetonitrile (0.083 mL, 0.316 mmol)were combined in toluene (0.75 mL) and the reaction mixture heated in a5 mL microwave vial at 120° C. for 30 min. The reaction mixture waspoured onto water (10 mL) and extracted with ethyl acetate (3×8 mL). Thecombined ethyl acetate layers were washed with brine (10 mL), driedthrough a hydrophobic frit and evaporated in vacuo to yield the crudeproduct (170 mg). The residue was dissolved in MeOH/DMSO (1:1, 2×1 mL)and purified by MDAP (High pH). The solvent was dried under a stream ofnitrogen to leave a white powder. The fractions were combined indichloromethane, evaporated in vacuo, sonicated with diethyl ether andevaporated once more to yield theproduct—N5-cyclobutyl-N3-methyl-1-(3-(methylamino)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(17 mg, 0.046 mmol, 46.0% yield) as an off white solid.

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=369.1.

Example 7:N5-Cyclobutyl-1-(3-(dimethylamino)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

N5-Cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (40mg, 0.160 mmol), (3-(dimethylamino)phenyl)methanol (0.034 mL, 0.241mmol) and 2-(tributylphosphoranylidene)acetonitrile (0.133 mL, 0.505mmol) were combined in toluene (1.2 mL) and the reaction mixture heatedin a 5 mL microwave vial at 120° C. for 30 min. The reaction wasreturned to the microwave for a further 30 min at 120° C. The reactionmixture was poured onto water (20 mL), and extracted with ethyl acetate(3×10 mL). The combined organic portions were evaporated in vacuo toyield the crude product as a brown oil. The sample was loaded inmethanol and purified by SPE on sulphonic acid (SCX) 5 g using thesequential solvents: methanol, 2M ammonia/methanol. The appropriatefractions were combined and evaporated in vacuo to give the crudeproduct (78 mg) as a brown glass. The sample was dissolved in MeOH/DMSO(1 mL, 1:1) and purified by MDAP (High pH). The solvent was evaporatedin vacuo to give a pale yellow solid (8.1 mg). This was loaded indichloromethane onto a 10 g SNAP silica cartridge and purified viaBiotage SP4 flash chromatography eluting from 10-40% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo to yieldN5-cyclobutyl-1-(3-(dimethylamino)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(6.3 mg, 0.016 mmol, 10.27% yield) as a pale yellow solid.

LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=383.4.

Example 8:1-Benzyl-N5-(3-fluorocyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2,4,6-Trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (53mg, 0.114 mmol), 3-fluorocyclobutanamine hydrochloride (29 mg, 0.231mmol), N,N-dimethylpyridin-4-amine (3 mg, 0.025 mmol), triethylamine(0.063 mL, 0.455 mmol) and THF (1 mL) were heated at 45° C. overnightunder N₂. The resulting off white suspension was concentrated to give100 mg of an off white solid. This was purified by chromatography onSiO₂ (Biotage SNAP 10 g cartridge, eluting with 0-100%ethylacetate/cyclohexane). The desired fractions were concentrated togive1-benzyl-N5-(3-fluorocyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(32 mg, 0.076 mmol, 66.9% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=358.

Examples 9-18: Amide Array ofN5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Monomers

Reagent Ex Reagent Reagent Volume No. Name Structure MW Mass (g) (mL)mmol  9 1- (Bromomethyl)- 3,5- dimethylbenzene

199.09 0.060 — 0.301 10 1- (Bromomethyl)- 4- methoxybenzene

201.06 0.061 — 0.301 11 8- (Bromomethyl) quinoline

222.08 0.067 — 0.301 12 1- (Bromomethyl)- 2,3- dimethylbenzene

199.08 0.060 — 0.301 13 1- (Bromomethyl)- 2-fluoro-3- methylbenzene

203.05 0.061 — 0.301 14 4- (Bromomethyl)- 1-fluoro-2- methylbenzene

203.05 0.061 — 0.301 15 4- (Bromomethyl)- 1-methoxy-2- methylbenzene

170.64 0.051 — 0.301 16 1- (Bromomethyl)- 3-fluoro-5- methylbenzene

203.05 0.061 — 0.301 17 1- (Bromomethyl)- 3- methylbenzene

185.06 0.056 — 0.301 18 2- (Bromomethyl)- 1-fluoro-4- methylbenzene

203.05 0.061 — 0.301

A stock solution ofN5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (475mg) dissolved in DMSO (11.4 mL) was made up. 0.6 mL of this solution wasadded to each of the listed bromide monomers (0.301 mmol). Potassiumcarbonate (41.6 mg, 0.301 mmol) was added to each of the reactionvessels and the reactions left stirring overnight. The samples were thenfiltered before purification. (N.B. Solubility issues in almost allsamples. Issue resolved by first adding 50 μL of ammonia to each sample.For the samples where this failed to resolve the issue, a drop of formicacid was added and the solutions re-filtered.) The samples were thendissolved in DMSO (0.8 mL) and purified by MDAP (High pH). The solventwas dried under a stream of nitrogen to give the required products aslisted in the subsequent table.

EXAMPLES

Mass Yield Ex No. Name Structure (mg) (%) [MH]⁺ Rt (min)*  9N5-Cyclobutyl-1- (3,5- dimethylbenzyl)- N3-methyl-2- oxo-1,2-dihydropyridine- 3,5- dicarboxamide

15 37 368 1.08 10 N5-Cyclobutyl-1- (4- methoxybenzyl)- N3-methyl-2-oxo-1,2- dihydropyridine- 3,5- dicarboxamide

15 36 370 0.94 11 N5-Cyclobutyl-N3- methyl-2-oxo-1- (quinolin-8-ylmethyl)-1,2- dihydropyridine- 3,5- dicarboxamide

12 27 391 0.97 12 N5-Cyclobutyl-1- (2,3- dimethylbenzyl)- N3-methyl-2-oxo-1,2- dihydropyridine- 3,5- dicarboxamide

 9 23 368 1.06 13 N5-Cyclobutyl-1- (2-fluoro-3- methylbenzyl)-N3-methyl-2- oxo-1,2- dihydropyridine- 3,5- dicarboxamide

 8 19 372 1.02 14 N5-Cyclobutyl-1- (4-fluoro-3- methylbenzyl)-N3-methyl-2- oxo-1,2- dihydropyridine- 3,5- dicarboxamide

11 27 372 1.03 15 N5-Cyclobutyl-1- (4-methoxy-3- methylbenzyl)-N3-methyl-2- oxo-1,2- dihydropyridine- 3,5- dicarboxamide

22 50 383 1.03 16 N5-cyclobutyl-1- (3-fluoro-5- methylbenzyl)-N3-methyl-2- oxo-1,2- dihydropyridine- 3,5- dicarboxamide

11 27 372 1.03 17 N5-Cyclobutyl-N3- methyl-1-(3- methylbenzyl)-2-oxo-1,2- dihydropyridine- 3,5- dicarboxamide

10 26 354 1.01 18 N5-Cyclobutyl-1- (2-fluoro-5- methylbenzyl)-N3-methyl-2- oxo-1,2- dihydropyridine- 3,5- dicarboxamide

 7 17 372 1.02 *All LCMS were conducted using 2 min High pH.

Example 19:1-Benzyl-N3-methyl-2-oxo-N5-(3-phenylcyclobutyl)-1,2-dihydropyridine-3,5-dicarboxamide

2,4,6-Trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (53mg, 0.114 mmol), N,N-dimethylpyridin-4-amine (3 mg, 0.025 mmol),3-phenylcyclobutanamine hydrochloride (39 mg, 0.212 mmol), triethylamine(0.06 mL, 0.430 mmol) and THF (1 mL) were stirred at 45° C. under N₂ for3 h. The reaction mixture was concentrated to give 140 mg of an offwhite solid which was purified by chromatography on SiO₂ (Biotage SNAP10 g cartridge, eluting with 0-100% ethylacetate/cyclohexane). Thedesired fractions were concentrated to give1-benzyl-N3-methyl-2-oxo-N5-(3-phenylcyclobutyl)-1,2-dihydropyridine-3,5-dicarboxamide(40 mg, 0.087 mmol, 76% yield) as a white solid.

LCMS (2 min Formic): Rt=1.12 min, [MH]⁺=416.

Example 20:N5-(6-Aminospiro[3.3]heptan-2-yl)-1-benzyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

tert-Butyl(6-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)spiro[3.3]heptan-2-yl)carbamate(75 mg, 0.152 mmol) was dissolved in DCM (5 mL), TFA (1 mL, 12.98 mmol)was added and the reaction stirred at rt under N₂ for 30 min. Thereaction mixture was concentrated and loaded onto a 2 g SCX cartridge(pre-conditioned with MeOH) and eluted with MeOH (40 mL) followed by 2MNH₃ in MeOH (40 mL). The ammonia fractions containing product werecombined and concentrated to giveN5-(6-aminospiro[3.3]heptan-2-yl)-1-benzyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(49.6 mg, 0.113 mmol, 74.6% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.55 min, [MH]⁺=395.

Example 21:(+/−)-N5-Cyclobutyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide

N5-Cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (50mg, 0.201 mmol), 1-phenylethanol (0.036 mL, 0.301 mmol) and2-(tributylphosphoranylidene)acetonitrile (0.166 mL, 0.632 mmol) werecombined in toluene (1.5 mL) and the reaction mixture heated in a 5 mLmicrowave vial at 120° C. for 30 min in a Biotage Initiator microwave.The reaction mixture was poured onto water (20 mL), and extracted withethyl acetate (3×10 mL). The combined organic portions were evaporatedin vacuo to yield the crude product as a brown oil. The residue wasloaded in dichloromethane onto a 25 g SNAP silica cartridge and purifiedvia Biotage SP4 flash chromatography eluting from 10-40% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo. The residue was dissolved in MeOH/DMSO (2×1 mL,1:1) and purified by MDAP (High pH, 2 injections). The relevantfractions were combined and evaporated in vacuo. The residue was loadedin dichloromethane onto a 10 g SNAP silica cartridge and purified viaBiotage SP4 flash chromatography, eluting from 20-100% ethylacetate/cyclohexane. The relevant fractions were combined and evaporatedin vacuo to yieldN5-cyclobutyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide(16 mg, 0.045 mmol, 22.57% yield) as a white solid.

LCMS (2 min Formic): Rt=0.97 min, [MH]⁺=354.0.

Example 22:1-Benzyl-N5-cyclobutyl-N3-cyclopropyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-Benzyl-5-bromo-N-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide(250 mg, 0.720 mmol), cobalt carbonyl (61.6 mg, 0.180 mmol), DMAP (176mg, 1.440 mmol), palladium (II) acetate (8.08 mg, 0.036 mmol),cyclobutanamine (0.123 mL, 1.440 mmol) and xantphos (20.83 mg, 0.036mmol) were added to a microwave vial. The vial was sealed and THF (3.3mL) added and the reaction heated in a Biotage Initiator microwave at80° C. for 40 min. The resulting mixture was diluted with water (20 mL)and extracted with ethyl acetate (20 mL). The organic layer was driedand concentrated under vacuum to give an orange residue. The residue wastaken up in DCM and purified by Biotage Isolera SNAP 50 g silica flashchromatography using a gradient of 0-100% cyclohexane/ethyl acetate. Theappropriate fractions were combined, concentrated under vacuum andpurified by MDAP (High pH). The product containing fractions werecombined and concentrated under vacuum to give the product (40 mg) as awhite solid.

LCMS (2 min Formic): Rt=1.02 min, [MH]⁺=366.3.

Example 23:1-((1H-Benzo[d]imidazol-4-yl)methyl)-N5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

tert-Butyl4-((5-(cyclobutylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate(54 mg, 0.113 mmol) was dissolved in DCM (2 mL) and trifluoroacetic acid(500 μL, 6.49 mmol) was added cautiously. The mixture was stirred at rtfor 90 min. The reaction mixture was loaded onto an SCX column, washedwith MeOH (2 CV) and then eluted with methanolic ammonia (2M) (4 CV).The appropriate fractions were combined and evaporated under reducedpressure to give a brown solid. The sample was dissolved in MeOH/DMSO (1mL, 1:1) and purified by MDAP (High pH). The solvent was evaporated invacuo to give the requiredproduct—1-((1H-benzo[d]imidazol-4-yl)methyl)-N5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(24 mg, 0.063 mmol, 56.2% yield) as a white solid.

LCMS (2 min Formic): Rt=0.97 min, [MH]⁺=354.0.

Example 24:1-Benzyl-N5-(2-cyclopropylethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Triethylamine (0.060 mL, 0.429 mmol), DMAP (6.56 mg, 0.054 mmol),2,4,6-trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (50mg, 0.107 mmol) and 2-cyclopropylethanamine (18.28 mg, 0.215 mmol) weredissolved in THF (1.5 mL) and stirred at 45° C. under nitrogen for 1 h.The reaction mixture was then concentrated under vacuum, loaded in DCMand purified by Biotage Isolera SNAP 25 g silica flash chromatographyusing a gradient of 0-100% cyclohexane/ethyl acetate. The productcontaining fractions were combined and concentrated under vacuum to givethe product (35 mg) as a white solid.

LCMS (2 min Formic): Rt=0.97 min, MH+=354.0.

Example 25: Methyl3-((5-(cyclobutylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate

N5-Cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (100mg, 0.401 mmol), methyl 3-(hydroxymethyl)benzoate (100 mg, 0.602 mmol)and 2-(tributylphosphoranylidene)acetonitrile (0.416 mL, 1.586 mmol)were combined in toluene (3 mL) and the reaction mixture heated in amicrowave vial at 120° C. for 30 min. The reaction mixture was pouredonto water (20 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic portions were washed with brine, dried through ahydrophobic frit and evaporated in vacuo to yield the crude product. Theresidue was loaded in dichloromethane onto a 25 g SNAP silica cartridgeand purified via Biotage SP4 flash chromatography, eluting from 10-50%(3:1 ethyl acetate:ethanol)/cyclohexane. The relevant fractions werecombined and evaporated in vacuo to yield a light brown solid (91 mg).The residue was dissolved in MeOH/DMSO (1 mL, 1:1) and purified by MDAP(High pH). The solvent was evaporated in vacuo to give the requiredproduct—methyl3-((5-(cyclobutylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate(44 mg, 0.111 mmol, 27.6% yield) as a white solid.

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=398.0.

Example 26:N5-Cyclobutyl-1-(3-(hydroxymethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A solution of methyl3-((5-(cyclobutylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate(35 mg, 0.088 mmol) in DCM (881 μL) was cooled to −78° C. and DIBAL-H(1M in toluene, 299 μL, 0.299 mmol) was added dropwise over 1 h. Afteran additional 1 h at −78° C. a supplementary portion of DIBAL-H (1M intoluene, 88 μL, 0.088 mmol) was added dropwise over 20 min. The reactionmixture was stirred for 70 min more. The reaction was quenched withmethanol (157 μL, 3.87 mmol) when still at −78° C. and then allowed towarm to ambient temperature. The reaction was diluted withdichloromethane (3 mL) and Rochelle's salt solution (3 mL) and stirredovernight. The layers were separated, and the aqueous phase wasextracted with dichloromethane (2×5 mL). The combined organic layerswere dried through a hydrophobic frit and evaporated in vacuo to yieldthe crude product (38 mg). The residue was loaded in dichloromethaneonto a 10 g SNAP silica cartridge and purified via Biotage SP4 flashchromatography, eluting from 15-75% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo toyield—N5-cyclobutyl-1-(3-(hydroxymethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(7 mg, 0.019 mmol, 21.52% yield) as a white solid.

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=370.3.

Example 27:N5-Cyclobutyl-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN5-cyclobutyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (100mg, 0.401 mmol) in methanol (535 μL) was added potassium carbonate (111mg, 0.802 mmol) and 1-(bromomethyl)-3-methoxybenzene (84 μL, 0.602mmol). The mixture was heated to 65° C. for 3 h. The reaction flask wasleft to stand overnight, during which time the solvent evaporated. Theresidue was diluted with H₂O (10 mL) and extracted with EtOAc (4×10 mL).The combined organics were washed with brine, dried through ahydrophobic frit and evaporated in vacuo to yield the crude product (188mg). The residue was loaded in dichloromethane and purified via BiotageSP4, eluting from 15-75% (3:1 ethyl acetate:ethanol)/cyclohexane. Therelevant fractions were recombined and evaporated in vacuo. The residueN5-cyclobutyl-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(142 mg, 0.384 mmol, 96% yield) was obtained as an off white solid.

LCMS (2 min Formic): Rt=0.93 min, [MH]⁺=370.3.

Example 28:N5-Cyclobutyl-1-(3-hydroxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN5-cyclobutyl-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(75 mg, 0.134 mmol) in dry dichloromethane at 0° C. was slowly addedBBr₃ (1M in dichloromethane, 402 μL, 0.402 mmol) under a nitrogenatmosphere. The mixture was stirred overnight while warming to rt. Afurther portion of BBr₃ (1M in dichloromethane, 402 μL, 0.402 mmol) wasadded and the reaction was stirred for a further 3 h. The reaction wasquenched by the careful addition of brine, and neutralized with sodiumbicarbonate. The mixture was diluted with water (10 mL) and the aqueouslayer was extracted with dichloromethane (12×10 mL). A thick emulsionformed during extraction and LCMS indicated the presence of product inthe aqueous phase. The aqueous phase was further extracted with ethylacetate (3×15 mL). The combined dichloromethane fractions were driedthrough a hydrophobic frit and evaporated in vacuo. The combined ethylacetate portions were washed with brine, dried through a hydrophobicfrit, added to the residue from the dichloromethane fractions andevaporated in vacuo. The crude residue (86 mg) was dry loaded inmethanol onto a 10 g SNAP silica cartridge and this was purified viaBiotage SP4 flash chromatography, eluting from 10-50% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo to yieldN5-cyclobutyl-1-(3-hydroxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(41 mg, 0.115 mmol, 86% yield) as a white solid.

LCMS (2 min Formic): Rt=0.76 min, [MH]⁺=356.2.

Example 29:N5-Cyclobutyl-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A solution of 1,3-dioxolan-2-one (28.6 mg, 0.325 mmol), potassiumcarbonate (40.8 mg, 0.295 mmol) andN5-cyclobutyl-1-(3-hydroxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(35 mg, 0.098 mmol), in DMF (0.985 mL) was stirred at 135° C. for 6 h.The reaction solution was partitioned between water (30 mL) and ethylacetate (10 mL). The aqueous phase was extracted further with ethylacetate (3×10 mL), and the combined organic portions were dried througha hydrophobic frit and evaporated in vacuo. The sample was dissolved inDMSO (1 mL) and purified by MDAP (High pH). The solvent was dried undera stream of nitrogen to give the requiredproduct—N5-cyclobutyl-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(28 mg, 0.070 mmol, 71.2% yield) as a white solid.

LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=400.2.

Example 30:1-((1H-Benzo[d]imidazol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

tert-Butyl4-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate(83 mg, 0.178 mmol) was dissolved in DCM (3.2 mL) and trifluoroaceticacid (783 μL, 10.16 mmol) was added cautiously. The mixture was stirredat rt for 90 min. The reaction mixture was loaded on an SCX column,washed with MeOH (2 CV) and eluted with methanolic ammonia (2M) (4 CV).The appropriate fractions were combined and evaporated under reducedpressure to give a brownsolid—1-((1H-benzo[d]imidazol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(60 mg, 0.164 mmol, 92% yield). 19 mg of the product was dissolved inmethanol (1 mL) and purified via MDAP (High pH). The relevant fractionswere blown down under a stream of nitrogen to give1-((1H-benzo[d]imidazol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(9 mg, 0.025 mmol, 13.81% yield).

LCMS (2 min Formic): Rt=0.43 min, [MH]⁺=366.1.

Example31:—(R)—N5-Cyclopropyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-3,5-dicarboxamide

HATU (95 mg, 0.250 mmol) was added to a solution of(R)-5-(methylcarbamoyl)-6-oxo-1-(1-phenylethyl)-1,6-dihydropyridine-3-carboxylicacid (50 mg, 0.166 mmol) and DIPEA (0.058 mL, 0.333 mmol) in DMF (0.5mL). The solution was stirred for 5 min and cyclopropylamine (0.014 mL,0.200 mmol) added. The resulting solution was stirred for 1 h. Thereaction mixture was purified by MDAP (Formic). The product containingfraction was azeotroped in vacuo to dryness with EtOH to give a whitesolid (50 mg).

LCMS (2 min TFA): Rt=0.85 min, [MH]⁺=340.1.

Example 32:N5-Cyclopropyl-N3-methyl-1-((1-methyl-1H-benzo[d]imidazol-7-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

KOH (15.2 mg, 0.271 mmol) was added to a solution of1-((1H-benzo[d]imidazol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(42 mg, 0.115 mmol) in DCM (2.5 mL) at rt under nitrogen. Methyl iodide(7.91 μL, 0.126 mmol) was added dropwise with vigorous stirring. After 1h a further portion of methyl iodide (7.19 μL, 0.115 mmol) and KOH (14.6mg, 0.260 mmol) were added. The reaction was stirred for 23 h. Thereaction was quenched with water (20.71 μL, 1.149 mmol), diluted withwater (10 mL) and the products were extracted with dichloromethane (4×10mL). The combined organic portions were dried through a hydrophobic fritand evaporated to dryness. The residue was dissolved in MeOH/DMSO (1 mL,1:1) and purified by MDAP (High pH). The solvent was dried under astream of nitrogen to give:N5-cyclopropyl-N3-methyl-1-((1-methyl-1H-benzo[d]imidazol-7-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(2.1 mg, 5.53 μmol, 4.82% yield) as a white solid.

LCMS (2 min Formic): Rt=0.40 min, [MH]⁺=380.2.

Example 33:(+/−)-1-Benzyl-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideand Example 114:(+/−)-1-Benzyl-N3-methyl-N5-((cis)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

DIPEA (0.275 mL, 1.572 mmol) was added to a suspension of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(150 mg, 0.524 mmol), 2-methylcyclopropanamine (74.5 mg, 1.048 mmol,commercially available from, for example UkrOrgSyntez), and HATU (299mg, 0.786 mmol) in DMF (4 mL). The reaction mixture was stirred at rtfor 30 min, after which time further HATU (299 mg, 0.786 mmol) and DIPEA(0.275 mL, 1.572 mmol) were added. The reaction was stirred for afurther 20 min. The reaction mixture was then partitioned between ethylacetate and water and the organic layer washed with 2× water. This waspassed through a hydrophobic frit and the solvent removed under reducedpressure. The resulting orange oil was dissolved in 1:1 DMSO:methanoland purified by MDAP. Two diastereomeric products were obtained fromMDAP. The solvent was removed under reduced pressure and the productswere left to dry in vacuo for 4 h to give:

(+/−)-1-benzyl-N3-methyl-N5-((cis)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(22.5 mg, 0.066 mmol, 12.65% yield) as a white solid

LCMS (2 min Formic): Rt=0.87 min, [MH]⁺=340.1.

(+/−)-1-benzyl-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(120 mg, 0.354 mmol, 67.5% yield) as a pale yellow solid.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=340.1.

Example 34:1-Benzyl-N5-((trans)-4-hydroxycyclohexyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(48 mg, 0.168 mmol), 4-aminocyclohexanol (44.1 mg, 0.383 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate (V) (HATU) (81 mg, 0.213 mmol) in DMF (1 mL) wasadded N,N-diisopropylethylamine (DIPEA) (0.059 mL, 0.335 mmol). Themixture was stirred at rt for 1.25 h before being concentrated under astream of nitrogen. The solution was made up to 1 mL with methanol anddirectly purified by MDAP (formic). The required fraction was evaporatedunder a stream of nitrogen before being dissolved in a 1:1 mixture ofdichloromethane/methanol (4 mL), concentrated under a stream of nitrogenand dried in vacuo to give the desired product as a pale yellow solid;1-benzyl-N5-((trans)-4-hydroxycyclohexyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(61.8 mg, 0.161 mmol, 96% yield).

LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=384.3.

Example 35:(+/−)-1-Benzyl-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

DIPEA (0.092 mL, 0.524 mmol) was added to a suspension of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(50 mg, 0.175 mmol), (2-aminocyclopropyl)methanol (30.4 mg, 0.349 mmol,commercially available from, for example, Enamine), and HATU (100 mg,0.262 mmol) in DMF (2 mL). The orange solution was stirred undernitrogen for 1 h and left to react overnight. Further(2-aminocyclopropyl)methanol (30.4 mg, 0.349 mmol), HATU (100 mg, 0.262mmol), and DIPEA (0.092 mL, 0.524 mmol) were added and the reactionmixture was stirred under nitrogen for a further 2 h. The reactionmixture was partitioned between ethyl acetate and water: the aqueouslayer was extracted with 2× ethyl acetate and the organic layer washedwith 2× water and passed through a hydrophobic frit. The solvent wasremoved under reduced pressure and the resulting orange oil wasdissolved in DCM. This was loaded onto a 10 g Biotage SNAP column, whichwas eluted in ethyl acetate:methanol (0-20%). The product-containingfractions were combined and the solvent removed under reduced pressure.The product was then left to dry in vacuo for 5 h to give1-benzyl-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(19.4 mg, 0.055 mmol, 31.3% yield) as a yellow solid.

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=356.1.

Example 36:(+/−)-1-Benzyl-N5-(2-methoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2-Methoxycyclopropanamine, HCl salt (30.4 mg, 0.349 mmol, commerciallyavailable from, for example, ZereneX) in DMF (2 mL) was added to amixture of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(50 mg, 0.175 mmol), HATU (100 mg, 0.262 mmol), and DIPEA (0.092 mL,0.524 mmol). The resulting brown solution was stirred under nitrogen for2 h. Further 2-methoxycyclopropanamine, HCl salt (30.4 mg, 0.349 mmol),HATU (100 mg, 0.262 mmol), and DIPEA (0.092 mL, 0.524 mmol) were addedand the reaction mixture was stirred under nitrogen for a further 1 hand left to react overnight. The reaction mixture was partitionedbetween ethyl acetate and water and the aqueous layer was extracted with2× ethyl acetate. The organic layer was washed with 2× water and 1×brine, passed through a hydrophobic frit, and the solvent removed underreduced pressure. The resulting orange oil was dissolved in DCM andloaded onto a 10 g Biotage SNAP column which was eluted withcyclohexane:ethyl acetate (50-100%). The product-containing fractionswere combined and the solvent removed under reduced pressure. The solidwas dissolved in DMSO:methanol (1:1) and purified by MDAP (Formic). Thesolvent was removed under reduced pressure and left to dry in vacuo for2 days to give1-benzyl-N5-(2-methoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(13.6 mg, 0.038 mmol, 21.91% yield) as a pale yellow solid.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=356.1.

Example 37:N5-Cyclopropyl-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a dry microwave vial, Pd(OAc)₂ (8 mg, 0.036 mmol), xantphos (14.5 mg,0.025 mmol) and DMAP (88 mg, 0.719 mmol) were added followed by dicobaltoctacarbonyl (36.9 mg, 0.108 mmol) and cyclopropylamine (50.7 μL, 0.719mmol). The vial was sealed immediately and placed under nitrogen.5-Bromo-1-(3-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(122 mg, 0.360 mmol) was added as a solution in 1,4-dioxane (2.5 mL) andthe vial was heated under microwave irradiation for 40 min at 80° C. Thereaction mixture was filtered through celite, concentrated in vacuo,taken up in ethyl acetate (30 mL) and washed with 2M HCl (10 mL). Theacid layer was extracted with ethyl acetate (2×10 mL). The combinedorganic portions were washed with brine (10 mL), dried through ahydrophobic frit and evaporated in vacuo. The crude residue (163 mg) wasloaded in dichloromethane onto a 25 g SNAP silica cartridge and purifiedvia Biotage SP4 flash chromatography, eluting with 15-75% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo to yield a yellow glass. The sample was dissolved inDMSO (1 mL) and purified by MDAP (High pH). The solvent was dried undera stream of nitrogen togive—N5-cyclopropyl-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(38 mg, 0.105 mmol, 29.2% yield) as a white solid.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=344.1.

Example 38:(+/−)-1-Benzyl-N5-(1-cyanocyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

DIPEA (0.183 mL, 1.048 mmol) was added to a suspension of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(100 mg, 0.349 mmol), 1-aminocyclopropanecarbonitrile, HCl salt (57.4mg, 0.699 mmol, commercially available from, for example,Sigma-Aldrich), and HATU (199 mg, 0.524 mmol) in DMF (2 mL). Thereaction mixture was stirred under nitrogen for 2 h. This was thenpartitioned between ethyl acetate and water, the aqueous layer extractedwith 2× ethyl acetate, and the organic layer washed with 2× water. Thiswas then passed through a hydrophobic frit and the solvent removed underreduced pressure. The resulting brown-orange oil was dissolved in DCMand loaded onto a 10 g Biotage SNAP column which was eluted withcyclohexane:ethyl acetate (20-80%). The product-containing fractionswere combined and the solvent removed under reduced pressure. The solidwas left to dry in vacuo overnight to give1-benzyl-N5-(1-cyanocyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(100 mg, 0.285 mmol, 82% yield) as a white solid.

LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=351.1.

Example 39:N5-Cyclopropyl-N3-methyl-2-oxo-1-(quinoxalin-5-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide

5-Bromo-N-methyl-2-oxo-1-(quinoxalin-5-ylmethyl)-1,2-dihydropyridine-3-carboxamide(50 mg, 0.134 mmol), cobalt carbonyl (14 mg, 0.041 mmol),cyclopropanamine (0.019 mL, 0.268 mmol), DMAP (33 mg, 0.270 mmol),palladium acetate (2 mg, 8.91 μmol) and Catacxium A (3 mg, 8.37 μmol)were combined in a microwave vial and de-gassed. 1,4-Dioxane (1.5 mL)was added and the vial was heated at 80° C. for 40 min. The resultingsolution was filtered through celite, partitioned between water andEtOAc, washed with 2M HCl, extracted with EtOAc (2×30 mL), dried over ahydrophobic frit and concentrated to give 70 mg of a green oil. This waspurified by chromatography on SiO₂ (Biotage SNAP 50 g cartridge, elutingwith 0-100% (25% ethanol in ethylacetate)/cyclohexane). The appropriatefractions were concentrated to give 10 mg of a yellow oil. This wasfurther purified by MDAP (Formic) and the appropriate fractions wereconcentrated to give the title product, 4 mg as a white solid.

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=376.

Example 40:(S*)-1-Benzyl-N5-(2,2-difluorocyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

DIPEA (0.183 mL, 1.048 mmol) was added to a solution of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(100 mg, 0.349 mmol), 2,2-difluorocyclopropanamine, HCl salt (65.0 mg,0.699 mmol, commercially available from, for example, ManchesterOrganics), and HATU (199 mg, 0.524 mmol) in DMF (3 mL). The reactionmixture was stirred under nitrogen for 3 h. The solvent was removedunder reduced pressure and the resulting orange oil was dissolved inDMSO/methanol (1:1). The solution was purified by MDAP (Formic) and theproduct-containing fractions were combined and the solvent removed underreduced pressure. The product was left to dry in vacuo overnight to give(+/−)-1-benzyl-N5-(2,2-difluorocyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(29 mg, 0.080 mmol, 22.98% yield) as a pale yellow solid. The racemicmixture was separated by achiral and chiral preparative HPLC:

Achiral Preparative Purification:

The sample was dissolved in DMSO (3 mL). 3000 μL injections were madeonto a CSH C18 150×30 mm, 5 μm. column using the chromatographicconditions: Solvent A: 10 mM ammonium bicarbonate in water adjusted topH 10 with ammonia solution, solvent B: acetonitrile, flow Rate: 40mL/min. Gradient: as below:

Time/min % B % A 0 10 90 3.5 10 90 25 30 70 32 30 70 35 99 1

Fractionation was determined by mixture of diode array & mass specsignal: UV detection: a summed signal from wavelengths 210 nm to 350 nm.MS: Waters ZQ, Ionisation mode: Alt Pos/Neg Electrospray, Scan Range:100 to 1000 AMU, Scan Time: 0.5 s, Inter scan Delay: 0.2 s. The flow andgradient was provided by a two pumps with a reduced flow passing throughthe injector during injection. The residual flow is introduced at thehead of the column so the overall flow remains constant. The fractionswere combined and dried under a stream of nitrogen blowdown at 40° C.and further purified by chiral purification.

Chiral Analytical Method:

Approx 0.5 mg of racemate was dissolved in 50% EtOH/Heptane (1 mL).Injection; 20 μL of the sample solution was injected onto the column(4.6 mm id×25 cm Chiralpak IC Lot No. IC00CE-OG021) eluting with 30%EtOH/heptane, at a rate of 1 mL/min and analysing at a wavelength of 215nm.

Chiral Preparative Method:

Approx 30 mg of racemate was dissolved in EtOH (2 mL). Injection; 2 mLof the sample solution was injected onto the column (30 mm×25 cmChiralpak IC Lot No. IC10028-01) eluting with 30% EtOH/heptane, at arate of 30 mL/min and analysing at a wavelength of 215 nm. Fractionsfrom 16-20 min were bulked and labelled peak 1. This gave the desiredsingle (unknown) enantiomer as a white solid (6 mg).

LCMS (2 min Formic): Rt=0.88 min, [MH]⁺=362.1.

Example 41: tert-Butyl(3-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclobutyl)carbamate

1-Benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(400 mg, 1.397 mmol) was taken up in DMF (9 mL) and HATU (584 mg, 1.537mmol) followed by DIPEA (0.488 mL, 2.79 mmol) were added. The reactionmixture was allowed to stir for 5 min, then tert-butyl(3-aminocyclobutyl)carbamate (260 mg, 1.397 mmol, commercially availablefrom, for example, Fluorochem) was added and the reaction allowed tostir for 1 h. The reaction mixture was concentrated under vacuum, loadedin DCM and purified by Biotage Isolera flash chromatography using a SNAP25 g silica cartridge, using a gradient of 0-100% ethylacetate/cyclohexane. The appropriate fractions were combined andconcentrated under vacuum. The solid obtained was dissolved in a minimumamount of DCM and purified by Biotage Isolera flash chromatography usinga SNAP 25 g silica cartridge, using a gradient of 0-100% ethylacetate/cyclohexane. The product containing fractions were combined andconcentrated under vacuum to give the desired product (530 mg, 1.166mmol, 83% yield) as a white solid.

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=455.2.

Example 42:N5-Cyclopropyl-1-(4-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a dry microwave vial,5-bromo-1-(4-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(123 mg, 0.363 mmol) and Pd(OAc)₂ (6.0 mg, 0.027 mmol) were added andtaken up in dry 1,4-dioxane (2.5 mL). Xantphos (13.3 mg, 0.023 mmol),DMAP (89 mg, 0.725 mmol) and cyclopropylamine (51.1 μL, 0.725 mmol) wereadded, followed by dicobalt octacarbonyl (37.2 mg, 0.109 mmol). The vialwas sealed immediately and heated under microwave irradiation for 40 minat 80° C. The reaction mixture was filtered through celite, concentratedin vacuo, taken up in ethyl acetate (30 mL) and washed with 2M HCl (10mL). The acid layer was extracted with ethyl acetate (2×10 mL). Thecombined organic portions were washed with brine (10 mL), dried througha hydrophobic frit and evaporated in vacuo. The crude residue (195 mg)was loaded in dichloromethane onto a 25 g SNAP silica cartridge andpurified via Biotage SP4 flash chromatography, eluting from 15-65% (3:1ethyl acetate:ethanol)/cyclohexane. The relevant fractions were combinedand evaporated in vacuo to yield a yellow glass. The sample wasdissolved in DMSO (1 mL) and purified by MDAP (High pH). The solvent wasdried under a stream of nitrogen to give a white solid. The solid wasfurther dried in vacuo overnight togive—N5-cyclopropyl-1-(4-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(47 mg, 0.130 mmol, 35.9% yield) as a white solid.

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=344.2.

Example 43:N5-Cyclopropyl-1-(4-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

5-Bromo-1-(4-methoxybenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(100 mg, 0.285 mmol), cobalt carbonyl (27 mg, 0.079 mmol),cyclopropanamine (0.04 mL, 0.577 mmol), DMAP (66 mg, 0.540 mmol),palladium acetate (3 mg, 0.013 mmol) and xantphos (8 mg, 0.014 mmol)were combined in a microwave vial and de-gassed. 1,4-Dioxane (3 mL) wasadded and the vial was heated at 80° C. for 40 min. The solution wasfiltered through celite, partitioned between water and EtOAc, washedwith 2M HCl, extracted with EtOAc (2×30 mL), dried over a hydrophobicfrit and concentrated to give 120 mg of a green oil. This was purifiedby chromatography on SiO₂ (Biotage SNAP 50 g cartridge, eluting with0-100% (25% ethanol in ethylacetate)/cyclohexane). The appropriatefractions were concentrated to give 60 mg of a brown oil. This waspurified by MDAP (Formic) and the appropriate fractions wereconcentrated to giveN5-cyclopropyl-1-(4-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(37 mg, 0.094 mmol, 32.9% yield) as a white solid.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=356.

Example 44:N5-Cyclopropyl-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (70 mg, 0.221 mmol) in DMF (2 mL) was added HATU (126 mg, 0.332mmol) followed by cyclopropanamine (26 mg, 0.455 mmol) and DIPEA (0.155mL, 0.885 mmol). The resulting reaction mixture was stirred at rt underN₂ for 7 h. The reaction mixture was concentrated to give 277 mg of ayellow oil and purified by chromatography on SiO₂ (Biotage SNAP 50 gcartridge, eluting with 40-100% EtOAc/cyclohexane). The appropriatefractions were concentrated to giveN5-cyclopropyl-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(97 mg, 0.232 mmol, 100% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=356.

Example 45:N5-Cyclopropyl-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Cyclopropanamine (0.041 mL, 0.597 mmol) in THF (1.5 mL) was added to asealed microwave vial containing5-bromo-N-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(100 mg, 0.298 mmol), DMAP (109 mg, 0.895 mmol), xantphos (8.63 mg,0.015 mmol), palladium acetate (3.34 mg, 0.015 mmol), and cobaltcarbonyl (25.5 mg, 0.075 mmol). The resulting suspension was heated to80° C. for 30 min by microwave irradiation. The blue reaction mixturewas partitioned between ethyl acetate (20 mL) and water (20 mL), theaqueous layer extracted with ethyl acetate (2×20 mL) and the organiclayer washed with water (2×20 mL) and brine (20 mL). This was dried overMgSO₄, filtered and the solvent removed under reduced pressure. Theyellow solid was dissolved in DCM and purified by 10 g Biotage SNAPsilica column using a gradient of 20-100% cyclohexane/ethyl acetate. Theproduct-containing fractions were combined and the solvent removed underreduced pressure. The product was left to dry in vacuo overnight to giveN5-cyclopropyl-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(52.7 mg, 0.155 mmol, 52.0% yield) as a yellow solid.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=340.1.

Example 46:1-Benzyl-N5-((1R*,2R*)-2-ethoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideand Example 47:1-Benzyl-N5-((1S*,2S*)-2-ethoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

DIPEA (0.549 mL, 3.14 mmol) was added to a suspension of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(300 mg, 1.048 mmol), 2-ethoxycyclopropanamine, HCl salt (212 mg, 2.096mmol, commercially available from, for example, Enamine), and HATU (598mg, 1.572 mmol) in DMF (5 mL). The resulting red solution was stirredunder nitrogen for 1.5 h. The reaction mixture was partitioned betweenethyl acetate and water, the aqueous layer was extracted with 2× ethylacetate, and the organic layer washed with 2× water and 1× brine. Thiswas passed through a hydrophobic frit and the solvent removed underreduced pressure. The resulting red oil was dissolved in DCM and loadedonto a 25 g Biotage SNAP silica column which was eluted withcyclohexane:ethyl acetate (30-100%). The product-containing fractionswere combined and the solvent removed under reduced pressure. Theproduct was left to dry in vacuo for 24 h to give(+/−)-(trans)-1-benzyl-N5-(2-ethoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(213.4 mg, 0.578 mmol, 55.1% yield) as a pale yellow solid. This racemicmixture was purified by chiral HPLC:

Analytical Method:

Approx 0.5 mg of the diastereomer was dissolved in 50% EtOH/Heptane (1mL). Injection; 20 μL of the sample solution was injected onto thecolumn (4.6 mm id×25 cm Chiralpak IC Lot No. IC00CE-OG021) eluting with30% EtOH/heptane, at a rate of 1 mL/min and analysing at a wavelength of215 nm.

Preparative Method:

Approx 200 mg of the diastereomer was dissolved in EtOH (4 mL).Injection: 2 mL of the sample solution was injected onto the column (30mm×25 cm Chiralpak IC Lot No. IC10028-01) eluting with 30% EtOH/heptane,at a rate of 30 mL/min and analysing at a wavelength of 215 nm.Fractions from 17-19 min were bulked and labelled peak 1. Fractions from21-25 min were bulked and labelled peak 2.

This gave the single enantiomer 1 (example 46) as a white solid (87 mg).

LCMS (2 min Formic): Rt=0.88 min, [MH]⁺=370.1.

This gave the single enantiomer 2 (example 47) as a white solid (71 mg).

LCMS (2 min Formic): Rt=0.88 min, [MH]⁺=370.2.

Example 48:(+/−)-1-Benzyl-N5-((trans)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

DIPEA (0.275 mL, 1.572 mmol) was added to a suspension of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(150 mg, 0.524 mmol), HATU (299 mg, 0.786 mmol), and(+/−)-(trans)-2-ethylcyclopropanamine (89 mg, 1.048 mmol, commerciallyavailable from, for example, Enamine) in DMF (3 mL). The reactionmixture was stirred for 20 min. The reaction mixture was partitionedbetween ethyl acetate and water and the organic layer washed with 2×water and 1× brine. This was passed through a hydrophobic frit and thesolvent removed under reduced pressure. The oil was dissolved in 1:1DMSO:methanol and purified by MDAP (TFA). The product-containingfractions were combined and the solvent removed under reduced pressure.The product was left to dry in vacuo for 4 h to give(+/−)-1-benzyl-N5-((trans)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(150.7 mg, 0.426 mmol, 81% yield) as a pale yellow solid.

LCMS (2 min Formic): Rt=0.99 min, [MH]⁺=354.1.

Example 49:N5-Cyclopropyl-1-(4-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

5-Bromo-1-(4-fluoro-3-methylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(180 mg, 0.510 mmol), cobalt carbonyl (43.6 mg, 0.127 mmol), DMAP (125mg, 1.019 mmol), palladium (II) acetate (5.72 mg, 0.025 mmol),cyclopropylamine (0.036 mL, 0.510 mmol) and xantphos (14.74 mg, 0.025mmol) were added to a microwave vial. The vial was sealed and THF (3.3mL) added and the reaction mixture then heated in a Biotage Initiatormicrowave at 90° C. for 30 min. The resulting mixture was diluted withwater (20 mL) and extracted with ethyl acetate (20 mL). The organiclayer was dried, concentrated under vacuum and purified by MDAP (HighpH). The appropriate fractions were combined and concentrated undervacuum to give the desired product (70 mg).

LCMS (2 min Formic): Rt=0.92 min, MH+=358.1.

Example 50:N5-Cyclopropyl-N3-methyl-2-oxo-1-(quinolin-8-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide

5-Bromo-N-methyl-2-oxo-1-(quinolin-8-ylmethyl)-1,2-dihydropyridine-3-carboxamide(220 mg, 0.591 mmol), cobalt carbonyl (50.5 mg, 0.148 mmol), DMAP (144mg, 1.182 mmol), palladium (II) acetate (6.63 mg, 0.030 mmol),cyclopropylamine (0.042 mL, 0.591 mmol) and xantphos (17.10 mg, 0.030mmol) were added to a microwave vial. The vial was sealed and THF (3.3mL) added and the reaction mixture was heated in a Biotage Initiatormicrowave at 80° C. for 30 min. The resulting mixture was diluted withwater (20 mL) and extracted with ethyl acetate (20 mL). The organiclayer was dried, concentrated under vacuum and purified by MDAP (HighpH). The appropriate fractions were combined to give the desired product(100 mg) as a white foam.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=377.1.

Example 51:1-((1H-Indazol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-((1H-Indazol-4-yl)methyl)-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(140 mg, 0.388 mmol), cobalt carbonyl (39 mg, 0.114 mmol),cyclopropanamine (0.05 mL, 0.722 mmol), DMAP (93 mg, 0.761 mmol),palladium acetate (5 mg, 0.022 mmol) and xantphos (11 mg, 0.019 mmol)were combined in a microwave vial and de-gassed. 1,4-Dioxane (3 mL) wasadded and the vial was heated at 80° C. for 40 min. The solution wasfiltered through celite, partitioned between water and EtOAc, washedwith 2M HCl, extracted with EtOAc (2×30 mL), dried over a hydrophobicfrit and concentrated to give 560 mg of a green/blue oil. This waspurified by chromatography on SiO₂ (Biotage SNAP 50 g cartridge, elutingwith 0-100% (25% ethanol in ethylacetate)/cyclohexane). The appropriatefractions were concentrated to give 27 mg of a white solid. This wasfurther purified by MDAP (Formic) and the appropriate fractions wereconcentrated to give1-((1H-indazol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(10 mg, 0.025 mmol, 6.35% yield) as a white solid.

LCMS (2 min Formic): Rt=0.67 min, [MH]⁺=366.

Example 52:1-((1H-Indazol-7-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-((1H-Indazol-7-yl)methyl)-5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(204 mg, 0.565 mmol), cobalt carbonyl (54 mg, 0.158 mmol),cyclopropanamine (0.08 mL, 1.155 mmol), DMAP (147 mg, 1.203 mmol),palladium acetate (6 mg, 0.027 mmol) and xantphos (14 mg, 0.024 mmol)were combined in a microwave vial and de-gassed. 1,4-Dioxane (4 mL) wasadded and the vial was heated at 80° C. for 40 min. The solution wasfiltered through celite, partitioned between water and EtOAc, washedwith 2M HCl, extracted with EtOAc (2×30 mL), dried over a hydrophobicfrit and concentrated to give 250 mg of a green oil. This was purifiedby chromatography on SiO₂ (Biotage SNAP 50 g cartridge, eluting with0-60% (25% ethanol in ethylacetate)/cyclohexane). The appropriatefractions were concentrated to give 114 mg of a yellow solid. This wasfurther purified by MDAP (Formic) and the appropriate fractions wereconcentrated to give1-((1H-indazol-7-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(38 mg, 0.094 mmol, 16.57% yield) as a white solid.

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=366.

Example 53:N5-Cyclopropyl-N3-methyl-1-(4-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a dry microwave vial,5-bromo-N-methyl-1-(4-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(120 mg, 0.358 mmol) and Pd(OAc)₂ (4.5 mg, 0.020 mmol) were added andtaken up in dry 1,4-dioxane (2.5 mL). Xantphos (15 mg, 0.026 mmol), DMAP(87 mg, 0.716 mmol) and cyclopropylamine (50.5 μL, 0.716 mmol) wereadded, followed by dicobalt octacarbonyl (36.7 mg, 0.107 mmol). The vialwas sealed immediately and heated under microwave irradiation for 40 minat 80° C. The vial was returned to the microwave for a further 20 min.The reaction mixture was filtered through celite, concentrated in vacuo,taken up in ethyl acetate (30 mL) and washed with 2M HCl (10 mL). Theacid layer was extracted with ethyl acetate (2×10 mL). The combinedorganic portions were washed with brine (10 mL), dried through ahydrophobic frit and evaporated in vacuo. The crude residue was loadedin dichloromethane onto a 25 g SNAP silica cartridge and purified viaBiotage SP4 flash chromatography, eluting from 15-65% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo to yield a yellow glass. The sample was dissolved inDMSO (1 mL) and purified by MDAP (High pH). The solvent was dried undera stream of nitrogen to give a white solid (68 mg). The sample wassubmitted for achiral purification chromatography:

The sample was dissolved in 3 mL of DMSO. 1500 μL injections were madeonto a CSH C18 150×30 mm, 5 μm column. Solvent A: 10 mM AmmoniumBicarbonate in water adjusted to pH 10 with Ammonia solution, solvent B:Acetonitrile, flow Rate: 40 mL/min. Gradient: as below:

Time/min % B % A 0 20 80 3 20 80 4 20 80 25 40 60 26 40 60

Fractionation was determined by mixture of diode array & mass specsignal: UV detection: a summed signal from wavelengths 210 nm to 350 nm.MS: Waters QDA, Ionisation mode: Positive Electrospray, Scan Range: 120to 800 AMU, Scan Time: 0.5 s, Inter scan Delay: 0.1 s. The flow andgradient was provided by a two pumps with a reduced flow passing throughthe injector during injection. The residual flow is introduced at thehead of the column so the overall flow remains constant. The fractionswere combined and dried under a stream of nitrogen blowdown at 40° C. toaffordN5-cyclopropyl-N3-methyl-1-(4-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(51 mg, 0.150 mmol, 42.0% yield) as a white solid.

LCMS (2 min Formic): Rt=0.89 min, [MH]⁺=340.1.

Example 54:N5-Cyclopropyl-1-(3,5-dimethylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

5-Bromo-1-(3,5-dimethylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(160 mg, 0.458 mmol), cobalt carbonyl (39.2 mg, 0.115 mmol), DMAP (112mg, 0.916 mmol), palladium (II) acetate (5.14 mg, 0.023 mmol),cyclopropylamine (0.032 mL, 0.458 mmol) and xantphos (13.26 mg, 0.023mmol) were added to a microwave vial. The vial was sealed and THF (3.3mL) added and the reaction mixture was heated in a Biotage Initiatormicrowave at 80° C. for 30 min. The resulting mixture was diluted withwater (20 mL) and extracted with ethyl acetate (20 mL). The organiclayer was dried, concentrated under vacuum and purified by MDAP (HighpH). The resulting product was loaded in DCM and purified by BiotageIsolera SNAP 10 g silica flash chromatography using a gradient of 0-60%cyclohexane/ethyl acetate. The product containing fractions werecombined and concentrated under vacuum to give the desired product (49mg) as a white solid.

LCMS (2 min Formic): Rt=0.98 min, [MH]⁺=354.1.

Example 55:N5-Cyclopropyl-1-(2-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

5-Bromo-1-(2-fluoro-3-methylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(200 mg, 0.566 mmol), cobalt carbonyl (48.4 mg, 0.142 mmol), DMAP (138mg, 1.133 mmol), palladium (II) acetate (6.36 mg, 0.028 mmol),cyclopropylamine (0.040 mL, 0.566 mmol) and xantphos (16.38 mg, 0.028mmol) were added to a microwave vial. The vial was sealed and THF (3.3mL) added and the reaction mixture was then heated in a BiotageInitiator microwave at 80° C. for 30 min. The resulting mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (20 mL). Theorganic layer was dried, concentrated under vacuum and purified by MDAP(High pH), the appropriate fractions were combined and concentratedunder vacuum. The resulting product was loaded in DCM and purified bypurified by Biotage Isolera SNAP 10 g silica flash chromatography usinga gradient of 0-60% cyclohexane/ethyl acetate. The product containingfractions were combined and concentrated under vacuum to give thedesired product (50 mg) as a white solid.

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=358.1.

Example 56:N5-Cyclopropyl-1-(2-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Cyclopropanamine (0.061 mL, 0.885 mmol) in THF (2 mL) was added to asealed microwave vial containing5-bromo-1-(2-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(150 mg, 0.442 mmol), cobalt carbonyl (42.0 mg, 0.111 mmol), xantphos(12.80 mg, 0.022 mmol), DMAP (162 mg, 1.327 mmol), and palladium acetate(4.95 mg, 0.022 mmol). The reaction mixture was heated to 80° C. for 30min by microwave irradiation. The reaction mixture was heated to 80° C.for a further 15 min by microwave irradiation. This was then heated to80° C. for a further 20 min by microwave irradiation. This was thenpartitioned between ethyl acetate (20 mL) and water (20 mL), the aqueouslayer extracted with ethyl acetate (2×20 mL) and the combined organiclayers then washed with water (2×20 mL). The organic layer was passedthrough a hydrophobic frit and the solvent removed under reducedpressure. The resulting orange oil was dissolved in DCM and purified byflash chromatography using a 25 g Biotage SNAP silica column and agradient of 0-100% cyclohexane/ethyl acetate. The product-containingfractions were combined and the solvent removed under reduced pressure.The product was left to dry in vacuo for 2 days to giveN5-cyclopropyl-1-(2-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(59.6 mg, 0.174 mmol, 39.2% yield) as a pale yellow solid.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=344.1.

Example 57:N5-Cyclopropyl-1-(2-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Cyclopropanamine (0.059 mL, 0.849 mmol) in THF (2 mL) was added to asealed microwave vial containing5-bromo-1-(2-fluoro-5-methylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(150 mg, 0.425 mmol), cobalt carbonyl (40.3 mg, 0.106 mmol), xantphos(12.29 mg, 0.021 mmol), palladium acetate (4.76 mg, 0.021 mmol), andDMAP (156 mg, 1.274 mmol). The reaction mixture was heated to 80° C. for30 min by microwave irradiation. This was heated to 80° C. for a further30 min by microwave irradiation. The reaction mixture was partitionedbetween ethyl acetate (20 mL) and water (20 mL), the aqueous layerextracted with ethyl acetate (2×20 mL) and the organic layer washed withwater (2×20 mL). This was passed through a hydrophobic frit and thesolvent removed under reduced pressure. The brown oil was dissolved inDCM and purified by flash chromatography using a 25 g Biotage SNAPsilica column and a gradient of 0-100% cyclohexane/ethyl acetate. Theproduct-containing fractions were combined, the solvent removed underreduced pressure, and the solid dissolved in DMSO/methanol (1:1). Thiswas purified by MDAP (Formic) and the solvent removed under reducedpressure. The product was left to dry in vacuo for 4 h to giveN5-cyclopropyl-1-(2-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(41.2 mg, 0.115 mmol, 27.1% yield) as a white solid.

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=358.1.

Example 58:1-((1H-Benzo[d]imidazol-6-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

N5-Cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (60mg, 0.255 mmol), 6-(bromomethyl)-1H-benzo[d]imidazole (88 mg, 0.417mmol), potassium carbonate (75 mg, 0.543 mmol) and DMF (2 mL) werestirred at 90° C. under N₂ overnight followed by a further 3 h. Theresulting suspension was concentrated and partitioned between EtOAc (20mL) and water (20 mL). The aqueous phase was extracted with EtOAc (2×20mL) and the combined organic layers were dried over a hydrophobic fritand concentrated to give 83 mg of a colourless oil. This was purified bychromatography on SiO₂ (Biotage SNAP 10 g cartridge, eluting with 0-100%(20% 2M NH₃ in MeOH in DCM)/DCM). The appropriate fractions wereconcentrated to give 12 mg of a white solid. This was further purifiedby MDAP (Formic). The appropriate fractions were concentrated to give1-((1H-benzo[d]imidazol-6-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(7 mg, 0.017 mmol, 6.76% yield) as a white solid.

LCMS (2 min Formic): Rt=0.40 min, [MH]+=366.

Example 59:N5-Cyclopropyl-N3-methyl-1-(3-(morpholinomethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide,Formic Acid Salt

To a dry microwave vial,5-bromo-N-methyl-1-(3-(morpholinomethyl)benzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(79 mg, 0.188 mmol) and N,N-dimethylpyridin-4-amine (46 mg, 0.377 mmol)were added and suspended in dry 1,4-dioxane (2 mL). Diacetoxypalladium(3 mg, 0.013 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8 mg, 0.014mmol) and cyclopropylamine (0.027 mL, 0.385 mmol) were added, followedby dicobalt octacarbonyl (20 mg, 0.058 mmol). The vial was sealed andheated under microwave irradiation for 40 min at 80° C. followed byheating at 80° C. for a further 30 min. The reaction mixture wasfiltered through a celite cartridge (2.5 g) and partitioned betweenethyl acetate and water. The organic layer was separated, dried (Na₂SO₄)and concentrated to give ˜82 mg of a crude yellow oil. This was purifiedby chromatography on SiO₂ (Biotage SNAP 10 g cartridge, eluting with0-10% of 2M NH₃ in MeOH/DCM over 330 mL). Fractions containing productwere concentrated in vacuo to give 10 mg of pale yellow oil. This wasdissolved in MeOH (2 mL) and loaded onto a 2 g SCX cartridge (pre-elutedwith MeOH) and eluted with MeOH (40 mL) followed by 2M NH₃ in MeOH (40mL). The ammonia fractions containing the desired product wereconcentrated in vacuo to give 8 mg of pale yellow oil. This was furtherpurified by MDAP (High pH) and the fractions containing the desiredproduct were concentrated to giveN5-cyclopropyl-N3-methyl-1-(3-(morpholinomethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide,formic acid salt (4 mg, 7.65 μmol, 4.07% yield) as a white solid.

LCMS (2 min High pH): Rt=0.80 min, [MH]⁺=425.

Example 60:1-Benzyl-N5-((1S,2S)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideand Example 84:1-Benzyl-N5-((1R,2R)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

DIPEA (0.842 mL, 4.82 mmol) was added to a suspension of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(897 mg, 3.13 mmol), (2-aminocyclopropyl)methanol (210 mg, 2.410 mmol,commercially available from, for example, Enamine), and HATU (1283 mg,3.37 mmol) in DMF (10 mL). The reaction mixture was stirred at rt for 90min, after which further HATU (1283 mg, 3.37 mmol) and DIPEA (0.842 mL,4.82 mmol) were added. The reaction was left to stand in solution for 2days. The reaction mixture was partitioned between ethyl acetate andwater and the aqueous layer extracted with 2× ethyl acetate. The organiclayer was washed with 2× water and 1× brine and then passed through ahydrophobic frit. The solvent was removed under reduced pressure and theresulting red oil was dissolved in DCM. This was loaded onto a 25 gBiotage SNAP silica column which was eluted in cyclohexane/ethyl acetate(0-100%). No product was seen in the fractions so the column was flushedwith ethyl acetate/methanol (0-20%). The product-containing fractionswere combined and the solvent removed under reduced pressure. Theresulting pale orange solid was dissolved in DMSO:methanol (1:1) andpurified by MDAP (TFA). The product-containing fractions were combinedand the solvent removed under reduced pressure. The product was left todry in vacuo for 1 h and submitted for chiral separation.

Analytical Method:

Approx 0.5 mg racemate dissolved in 50% EtOH/Heptane (1 mL). Injection;20 μL of the sample solution was injected onto column (4.6 mmid×25 cmChiralpak IA Lot No. IA00CE-KL030) eluting with 40% EtOH/heptane, at arate of 1 mL/min and analysing with a wavelength of 215 nm.

Preparative Method:

Approx 266 mg racemate dissolved in EtOH (4 mL)+heat. Injection; 2 mL ofthe sample solution was injected onto column (30 mm×25 cm Chiralpak IALot No. IA11321-01) eluting with 40% EtOH/heptane, at a rate of 30mL/min and analysing with a wavelength of 215 nm. Fractions from 17-22min were bulked and labelled peak 1. This isomer contained a relatedimpurity which ran on the front of the isomer. Fractions from 25.5-38min were bulked and labelled peak 2. The bulked fractions were vac'eddown using a rotary evaporator and then transferred to a weighed flaskfor final analysis as described by the analytical method above.

Peak 1: This gave the single enantiomer as a pale yellow solid (129 mg),but this was shown to be impure.

Peak 2: This gave the single enantiomer (Example 60) as a pale yellowsolid (86 mg).

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=356.1.

The sample corresponding to peak 1 was further purified by achiralpreparative HPLC:

Achiral Purification

The sample was dissolved in DMSO (6 mL). 3000 μL injections were madeonto a Xselect CSH C18 (150 mm×30 mm, 5 μm) column using thechromatographic conditions: Solvent A: 0.1% v/v solution of Formic Acidin Water, solvent B: 0.1% v/v solution of Formic Acid in Acetonitrile,flow Rate: 40 mL/min. Gradient: as below:

Time/min % B % A 0 10 90 3.5 10 90 25 30 70 32 30 70 35 99 1

Fractionation was determined by mixture of diode array & mass specsignal: UV detection: a summed signal from wavelengths 210 nm to 350 nm.MS: Waters SQ, Ionisation mode: Alt Pos/Neg Electrospray, Scan Range:100 to 1000 AMU, Scan Time: 0.5 s, Inter scan Delay: 0.2 s. The flow andgradient was provided by a two pumps with a reduced flow passing throughthe injector during injection. The residual flow is introduced at thehead of the column so the overall flow remains constant. The fractionswere combined and dried under a stream of nitrogen blowdown at 40° C.This gave the single enantiomer (Example 84) as a white solid (89 mg).

LCMS (2 min Formic): Rt=0.73 min, [MH]⁺=356.1.

Example 61:(+/−)-1-(2-Fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

THF (2.5 mL) was added to a sealed microwave vial containing5-bromo-1-(2-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(150 mg, 0.442 mmol), palladium acetate (4.95 mg, 0.022 mmol), cobaltcarbonyl (42.0 mg, 0.111 mmol), (+/−)-(trans)-2-methylcyclopropanamine(62.9 mg, 0.885 mmol, commercially available from, for example,Fluorochem), xantphos (12.80 mg, 0.022 mmol), and DMAP (162 mg, 1.327mmol). The reaction mixture was heated to 80° C. for 40 min by microwaveirradiation. The reaction mixture was heated to 80° C. for a further 35min by microwave irradiation. The reaction mixture was partitionedbetween ethyl acetate (20 mL) and water (20 mL), the aqueous layer wasextracted with ethyl acetate (2×20 mL), and the organic layer washedwith water (2×20 mL) and brine (20 mL). This was passed through ahydrophobic frit and the solvent removed under reduced pressure. Theresulting orange oil was dissolved in DCM and purified by flashchromatography using a 25 g Biotage SNAP silica column and a gradient of10-100% ethyl acetate/cyclohexane. The fractions were combined, thesolvent removed in vacuo, and the product dissolved in DMSO:methanol(1:1) and purified by MDAP (Formic). The product-containing fractionswere combined and the solvent removed under reduced pressure. Theproduct was left to dry in vacuo for 2 h to give1-(2-fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(60.2 mg, 0.168 mmol, 38.1% yield) as a white solid.

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=358.1.

Example 62:5-Bromo-1-((6-methoxypyridin-3-yl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

5-Bromo-1-((6-methoxypyridin-3-yl)methyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(150 mg, 0.426 mmol), cobalt carbonyl (36.4 mg, 0.106 mmol), DMAP (104mg, 0.852 mmol), palladium (II) acetate (4.78 mg, 0.021 mmol),cyclopropanamine (24.32 mg, 0.426 mmol) and xantphos (12.32 mg, 0.021mmol) were added to a microwave vial. The vial was sealed, THF (3.3 mL)added and the reaction mixture was heated in a Biotage Initiatormicrowave at 80° C. for 30 min. The resulting mixture was diluted withwater (20 mL) and extracted with ethyl acetate (20 mL). The organiclayer was dried, concentrated under vacuum and purified by MDAP (HighpH), the appropriate fractions were combined and concentrated undervacuum. The resulting product was loaded in DCM and purified by BiotageIsolera SNAP 10 g silica flash chromatography using a gradient of 0-60%cyclohexane/ethyl acetate. The product containing fractions werecombined and concentrated under vacuum to give the product (64 mg) as awhite solid.

LCMS (2 min Formic): Rt=0.72 min, [MH]⁺=357.1

Example 63: (+/−)1-(2-Fluoro-5-methylbenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

5-Bromo-1-(2-fluoro-5-methylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(150 mg, 0.425 mmol), cobalt carbonyl (36.3 mg, 0.106 mmol), DMAP (104mg, 0.849 mmol), palladium (II) acetate (4.77 mg, 0.021 mmol),(+/−)-(trans)-2-methylcyclopropanamine (30.2 mg, 0.425 mmol,commercially available from, for example, UkrOrgSynthesis Ltd.) andxantphos (12.29 mg, 0.021 mmol) were added to a microwave vial. The vialwas sealed and THF (3.3 mL) added and the reaction mixture was heated ina Biotage Initiator microwave at 80° C. for 30 min. The resultingmixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL). The organic layer was dried, concentrated under vacuum andpurified by MDAP (High pH). The product containing fractions werecombined and concentrated under vacuum to give the product (67 mg) as abrown solid.

LCMS (2 min Formic): Rt=0.99 min, MH+=372.1.

Example 64:1-Benzyl-N5-((1R,2R)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideand Example 65:1-benzyl-N5-((1S,2S)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-Benzyl-N5-(((+/−)-trans)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(for example, example 48, ˜148 mg) was submitted for chiral separation:

Analytical Method:

Approx 0.5 mg racemate was dissolved in 50% EtOH/heptane (1 mL).Injection; 20 μL of the sample solution was injected onto the column(4.6 mmid×25 cm Chiralcel OJ-H Lot No. OJH0CE-QL055) eluting with 15%EtOH/heptane at a rate of 1 mL/min and analysing with a wavelength of215 nm.

Preparative Method:

Approx 144 mg racemate was dissolved in EtOH (3 mL)+heat. Injection; 1.5mL of the sample solution was injected onto the column (2 cm×25 cmChiralcel OJ Lot No. OJ00CJ-PD002) eluting with 15% EtOH/heptane at arate of 15 mL/min and analysing with a wavelength of 215 nm. Fractionsfrom 8-11 min were bulked and labelled peak 1; fractions from 11-13 minwere bulked and labelled mix; fractions from 13-20 min were bulked andlabelled peak 2. The mix fractions were bulked, vac'ed down andreprocessed using the prep method above.

This gave the enantiomer 1 (example 64) as a pale yellow solid (67 mg).

LCMS (2 min Formic): Rt=0.99 min, [MH]⁺=354.1.

This gave the enantiomer 2 (example 65) as a pale yellow solid (65 mg).

LCMS (2 min Formic): Rt=0.99 min, [MH]⁺=354.1.

Example 66:1-((1H-Indol-7-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN5-cyclopropyl-N3-methyl-2-oxo-1-((1-tosyl-1H-indol-7-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(124 mg, 0.120 mmol) in methanol (399 μL) and THF (797 μL) stirred undernitrogen at rt, was added solid cesium carbonate (117 mg, 0.359 mmol) inone charge. The reaction mixture was stirred at 70° C. for 1 h. Thereaction mixture was concentrated in vacuo before being taken up indichloromethane (20 mL) and water (15 mL). The aqueous phase wasacidified with 2M HCl (1 mL) and extracted with dichloromethane (5×10mL). The combined organics were dried through a hydrophobic frit andevaporated in vacuo to yield the crude product (99 mg). The sample wasdissolved in MeOH/DMSO (1 mL, 1:1) and purified by MDAP (Formic). Thesolvent was dried under a stream of nitrogen to give a white solid (55mg). The sample was dissolved in 9 mL of DMSO. 3000 μL injections weremade onto a CSH C18 150×30 mm, 5 μm. column using the chromatographicconditions listed. Solvent A: 0.1% TFA acid in water, solvent B: 0.1%TFA in Acetonitrile, flow Rate: 40 mL/min. Gradient: as below:

Time/min % B % A 0 20 80 3.5 20 80 25 40 60 32 40 60 35 99 1

Fractionation was determined by mixture of diode array & mass specsignal: UV detection: a summed signal from wavelengths 210 nm to 350 nm.MS: Waters ZQ, Ionisation mode: Positive Electrospray, Scan Range: 100to 1000 AMU, Scan Time: 0.5 s, Inter scan Delay: 0.2 s. The flow andgradient was provided by a two pumps with a reduced flow passing throughthe injector during injection. The residual flow is introduced at thehead of the column so the overall flow remains constant. The fractionswere combined and dried under a stream of nitrogen blowdown at 40° C. toprovide two still impure sample.

Sample 1=11.8 mg (Purity: 80%), Sample 2=57 mg (Purity: 83%).

The impure samples were recombined and purified by chiral preparativeHPLC:

Analytical Method:

Approx 0.5 mg sample was dissolved in 50% EtOH/Heptane (1 mL). 20 μL wasinjected onto column (Column 4.6 mmid×25 cm Chiralpak IC, Lot No.IC00CE-OG021) which was eluted with 40% EtOH (+0.2%isopropylamine)/Heptane, flow rate=1.0 mL/min, detection wavelength=215nm, 4. Ref 550, 100

Preparative Method:

Approx 68 mg sample was dissolved in EtOH (4 mL). Injection; 2 mL of thesolution was injected onto the column (Column: 30 mm×25 cm Chiralpak,Lot No IC10028-01) which was eluted with 40% EtOH (+0.2%isopropylamine)/Heptane (+0.2% isopropylamine), flow rate=30 mL/min,detection wavelength, 215 nm, 4. Ref 550, 100. Total number ofinjections=2. Fractions from 10-11 min were bulked and labelled peak 1.Fractions from 15-18 min were bulked and labelled peak 2. The bulkedfractions were vac'ed down using a rotary evaporator and thentransferred to a weighed flask for final analysis as described by theanalytical method above. Peak 2 the desired product was further dried invacuo toyield—1-((1H-indol-7-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(18.8 mg, 0.049 mmol, 41.0% yield) as a white solid.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=365.1.

Example 67:1-((1H-Indol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN5-cyclopropyl-N3-methyl-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(208 mg, 0.160 mmol) in methanol (535 μL) and THF (1.070 mL) stirredunder nitrogen at rt, was added solid cesium carbonate (157 mg, 0.481mmol) in one charge. The reaction mixture was stirred at rt for 40 min.The temperature was increased to 70° C. and stirring continued for 1 h.The reaction mixture was concentrated in vacuo and the residue was takenup in water (15 mL) and dichloromethane (10 mL). The aqueous layer wasextracted with dichloromethane (8×10 mL), and the combined organics weredried through a hydrophobic frit and evaporated in vacuo. LCMS revealedresidual product in the aqueous phase, which was acidified with 2M HCl(1 mL) and extracted further with dichloromethane (3×10 mL). Thecombined organics were dried through a hydrophobic frit and evaporatedin vacuo. The crude residue (136 mg) was submitted for chiralpurification chromatography.

Analytical Method:

Approx 0.5 mg sample was dissolved in 50% EtOH/Heptane (1 mL). 20 μL wasinjected onto column (Column: 4.6 mm id×25 cm Chiralpak IC, Lot No.IC00CE-OG021) which was eluted with 40% EtOH (+0.2%isopropylamine)/heptane, flow rate=1.0 mL/min, detection wavelength=215nm, 4. Ref 550, 100

Preparative Method:

Approx 135 mg sample was dissolved in EtOH (5 mL)+heat and centrifuge.Injection: 2.5 mL of the solution was injected onto the column (Column:30 mm×25 cm Chiralpak, Lot No IC10028-01) which was eluted with 40% EtOH(+0.2% isopropylamine)/heptane (+0.2% isopropylamine), flow rate=30mL/min, detection wavelength, 215 nm, 4. Ref 550, 100. Total number ofinjections=2. Fractions from 9.5-10.5 min were bulked and labelledpeak 1. Fractions from 12.5-14 min were bulked and labelled peak 2. Thebulked fractions were vac'ed down using a rotary evaporator and thentransferred to a weighed flask for final analysis as described by theanalytical method above. Peak 2 was the desired product and was dried invacuo toafford—1-((1H-indol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(52.8 mg, 0.138 mmol, 86% yield) as a white solid.

LCMS (2 min Formic): Rt=0.79 min, [MH]⁺=365.1.

Example 68:1-(3-Chlorobenzyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

5-Bromo-1-(3-chlorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(220 mg, 0.619 mmol), cobalt carbonyl (52.9 mg, 0.155 mmol), DMAP (151mg, 1.237 mmol), palladium (II) acetate (6.94 mg, 0.031 mmol),cyclopropanamine (0.044 mL, 0.619 mmol) and xantphos (17.90 mg, 0.031mmol) were added to a microwave vial. The vial was sealed and THF (3 mL)added and the reaction mixture was heated in a Biotage Initiatormicrowave at 80° C. for 30 min. The resulting mixture was diluted withwater (20 mL) and extracted with ethyl acetate (20 mL). The organiclayer was dried, concentrated under vacuum and purified by MDAP (HighpH). The product containing fractions were combined and concentratedunder vacuum to give the product (81 mg) as a white solid.

LCMS (2 min Formic): Rt=0.92 min, [MH]⁺=360.0.

Examples 69-74: Amide Array of1-(3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Monomers

Reagent Ex Reagent Reagent Volume No. Name Structure MW Mass (g) (mL)mmol 69 rac-trans-2- methylcyclo- propanamine

 45.08 0.0085 — 0.120 70 2- cyclopropyl- ethanamine

 85.15 0.0102 — 0.120 71 tert-butyl (6- aminospiro[3.3] heptan-2-yl)carbamate

226.32 0.016 — 0.071 72 3- fluorocyclo- butanamine hydrochloride

125.57 0.0151 — 0.120 73 2- (ethoxymethyl) cyclo- propanamine

101.15 0.0121 — 0.120 74 (2- aminocyclo- propyl)methanol

 87.12 0.0105 — 0.120

To a stock solution of1-(3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (300 mg, 1.0 mmol) and HATU (380 mg, 1.0 mmol) dissolved in DMF (5mL) was added DIPEA (520 μL, 3.0 mmol). The mixture was shaken andsonicated to aid dispersion. An aliquot (0.5 mL) of this mixture wasadded to the appropriate amine (0.12 mmol) in a vial which wassubsequently sealed. NOTE: to the reaction containing the monomer amineused to prepare example 72 was added additional DIPEA (50 μL, 0.286mmol). Each vial was shaken before being allowed to stand at rt for 18h. NOTE: to the reaction containing monomer amine used to prepareexample 71 was added further HATU (0.038 g, 0.100 mmol) and DIPEA (0.052mL, 0.300 mmol) before this mixture was left to stand at room temp for 1h. The samples were injected as is and purified by MDAP (High pH). Thesolvent was dried under a stream of nitrogen in the plate blowdownapparatus to give the required products. The product derived from themonomer amine used to prepare example 69 was determined to still haveimpurities present and so was repurified by being dissolved in MeOH:DMSO(1 mL, 1:1) and purified by MDAP (High pH). The solvent was evaporatedunder a stream of nitrogen to give the required product. The productderived from the amine monomer used to prepare example 71 was dissolvedin DCM (0.5 mL), TFA (0.5 mL) was added and the vial was capped andsonicated to aid dispersion. The mixture was left to stand at rt for 2 hand then the solvent was removed. The residue was redissolved in MeOH(0.5 mL) and applied to the top of a SCX-2 SPE cartridge (100 mg,preconditioned with MeOH (1 mL)). The cartridge was eluted with furtherMeOH (1 mL) followed by 2M NH₃/MeOH (1 mL). The solvent was dried undera stream of nitrogen in the plate blowdown apparatus to give therequired products as shown in the table below.

EXAMPLES

Ex Mass Yield Rt No. Name Structure (mg) (%) [MH]⁺ (min)* 69rac-N3-methyl-1-(3- methylbenzyl)-N5- ((1R,2R)-2- methylcyclopropyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

 3.7 7.9 354 0.94 70 N5-(2- cyclopropylethyl)- N3-methyl-1-(3-methylbenzyl)-2- oxo-1,2- dihydropyridine-3,5- dicarboxamide

13.6 28 368 1.00 71 N5-(6- aminospiro[3.3] heptan-2-yl)-N3- methyl-1-(3-methylbenzyl)- 2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

12.7 40 409 0.58 72 N5-(3- fluorocyclobutyl)- N3-methyl-1-(3-methylbenzyl)-2- oxo-1,2- dihydropyridine-3,5- dicarboxamide

20.8 42 372 0.92 73 N5-(2- ethoxycyclopropyl)- N3-methyl-1-(3-methylbenzyl)-2- oxo-1,2- dihydropyridine-3,5- dicarboxamide

20.9 41 384 0.92 74 N5-(2-(hydroxy- methyl)cyclopropyl)- N3-methyl-1-(3-methylbenzyl)- 2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

11.5 28 370 0.77 *All LCMS were conducted using 2 min Formic.

Examples 75-79: Amide Array of(R)-5-(methylcarbamoyl)-6-oxo-1-(1-phenylethyl)-1,6-dihydropyridine-3-carboxylicacid

To a stock solution of(R)-5-(methylcarbamoyl)-6-oxo-1-(1-phenylethyl)-1,6-dihydropyridine-3-carboxylicacid (30 mg, 0.1 mmol) and HATU (380 mg) in DMF (5 mL) was added DIPEA(520 μL). The mixture was shaken and sonicated to aid dispersion. Themixture was aliquoted (0.5 mL) to a set of preweighed amines (0.100mmol) in micronic vials. These were capped and shaken and left to standat rt for 18 h. The samples were purified by MDAP (High pH). The solventwas dried under a stream of nitrogen to give the required products.Example 75 had additional DIPEA (50 μL) added to the reaction mixture onaddition of the DIPEA.

Reagent Ex Reagent Volume No. Reagent Name Structure MW Mass (g) (mL)mmol 75 3- fluorocyclo- butanamine hydrochloride

125.57 0.015 — 0.100 76 2- cyclopropyl- ethanamine

 85.15 0.010 — 0.100 77 rac-2- ethoxycyclo- propanamine

101.15 0.012 — 0.100 78 rac-(2- aminocyclopropyl) methanol

 87.12 0.010 — 0.100 79 (+/−)-(trans)-2- methylcyclo- propanamine

 71.12 0.007 0.100

Ex Mass Yield Rt no. Name Structure (mg) (%) [MH]+ (min) 75 (R)-N5-(3-fluorocyclobutyl)- N3-methyl-2-oxo- 1-(1- phenylethyl)-1,2-dihydropyridine- 3,5- dicarboxamide

11 26.7 371.9 0.91 76 (R)-N5-(2- cyclopropylethyl)- N3-methyl-2-oxo-1-(1- phenylethyl)-1,2- dihydropyridine- 3,5- dicarboxamide

22.4 54.9 368.0 0.99 77 N5-(2- ethoxycyclopropyl)- N3-methyl-2-oxo-1-((R)-1- phenylethyl)-1,2- dihydropyridine- 3,5- dicarboxamide

20.8 48.8 383.9 0.90 78 N5-(2- (hydroxymethyl) cyclopropyl)-N3-methyl-2-oxo-1- phenylethyl)-1,2- dihydropyridine- 3,5- dicarboxamide

3.2  7.8 369.9 0.75 79 N3-methyl-N5- ((trans)-2- methylcyclopropyl)-2-oxo-1-((R)- 1-phenylethyl)- 1,2- dihydropyridine- 3,5- dicarboxamide

19.6 49.9 354.0 0.92

All LCMS were conducted using 2 min Formic method.

Example 80:N5-Cyclopropyl-N3-methyl-2-oxo-1-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide,hydrochloride

tert-Butyl7-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate(100 mg, 0.202 mmol) and TFA (1 mL, 12.98 mmol) were stirred at rt inDCM (4 mL) for 30 min. The reaction mixture was concentrated and loadedonto a 5 g SCX cartridge (pre-conditioned with MeOH) and eluted withMeOH (20 mL) followed by 2M NH₃ in MeOH (20 mL). Ammonia fractionscontaining product were combined and concentrated to give 79 mg of acolourless oil. This was further purified by MDAP (Formic). Theappropriate fractions were partitioned between DCM (30 mL) and sat.sodium bicarbonate solution (30 mL), the aqueous layer was extractedwith DCM (2×30 mL) and further extracted with 5% MeOH in DCM (3×30 mL),the combined organic layers were dried over a hydrophobic frit andconcentrated to give 104 mg of a white solid. This was further purifiedby MDAP (High pH). The appropriate fractions were concentrated to giveN5-cyclopropyl-N3-methyl-2-oxo-1-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(44 mg, 0.100 mmol, 49.7% yield) as a colourless oil. This was dissolvedin MeOH (1 mL) and 1M HCl in diethyl ether (0.11 mL, 0.110 mmol) wasadded and the sample blown down to giveN5-cyclopropyl-N3-methyl-2-oxo-1-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide,hydrochloride (42 mg, 0.088 mmol, 43.4% yield) as an orange solid

LCMS (2 min Formic): Rt=0.46 min, [MH]⁺=395.

Example 81:1-Benzyl-N5-(2-((cis)-4-hydroxycyclohexyl)ethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideand Example 85:1-Benzyl-N5-(2-((trans)-4-hydroxycyclohexyl)ethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(50.1 mg, 0.175 mmol), 4-(2-aminoethyl)cyclohexanol (53.9 mg, 0.376mmol, commercially available from, for example, TCI) and HATU (80.5 mg,0.212 mmol) in DMF (1 mL) was added DIPEA (0.061 mL, 0.350 mmol). Themixture was stirred at rt for 1.25 h. Further HATU (43 mg, 0.113 mmol)and DIPEA (0.0305 mL, 0.175 mmol) were added and stirring continued for1 h. The reaction mixture was then concentrated under a stream ofnitrogen before being made up to 2 mL with a 2:1 mixture ofDMSO/methanol and directly purified by MDAP (Formic). The requiredfractions for the two diastereomeric products were separatelyconcentrated under a stream of nitrogen.

Cis-isomer: was further dried in vacuo to give a white solid1-benzyl-N5-(2-((cis)-4-hydroxycyclohexyl)ethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(33.9 mg, 0.082 mmol, 47.1% yield).

LCMS (2 min Formic): Rt=0.86 min, [MH]⁺=412.2.

Trans-isomer: was dissolved in DMSO (1 mL) and re-purified by MDAP(Formic). The required fraction was concentrated under a stream ofnitrogen before being dissolved in a 1:1 mixture ofdichloromethane/methanol, concentrated under a stream of nitrogen anddried in vacuo to give as a white solid,1-benzyl-N5-(2-((trans)-4-hydroxycyclohexyl)ethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(19.9 mg, 0.048 mmol, 27.6% yield).

LCMS (2 min formic): Rt=0.84 min, [MH]⁺=412.2.

Example 82:(+/−)-1-(4-Fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(4-Fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.657 mmol) was taken up in DMF (5 mL) and HATU (275 mg,0.723 mmol) was added followed by DIPEA (0.230 mL, 1.315 mmol). Thereaction mixture was allowed to stir for 5 min, then(+/−)-(trans)-2-methylcyclopropanamine (46.7 mg, 0.657 mmol) was addedand the reaction allowed to stir for 1 h. The reaction mixture was takenup in ethyl acetate (20 mL). The organic layer was washed with sat. aq.sodium bicarbonate (20 mL) and water (20 mL). The organic layers werecombined and concentrated under vacuum. The solid was taken up in DCMand purified by Biotage Isolera flash chromatography using a SNAP 25 gsilica cartridge, using a gradient of 0-60% EtOAc/cyclohexane. Theappropriate fractions were combined and concentrated under vacuum togive the desired product (152 mg) as a white solid.

LCMS (2 min Formic): Rt=0.92 min, [MH]⁺=358.1.

Example 83:1-(2-Fluorobenzyl)-N5-((1S*,2S*)-2-methoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

THF (2.3 mL) was added to a sealed microwave vial containing5-bromo-1-(2-fluorobenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide(120 mg, 0.354 mmol), 2-methoxycyclopropanamine, HCl salt (46.2 mg,0.531 mmol, commercially available from, for example, ZereneX),palladium acetate (3.96 mg, 0.018 mmol), cobalt carbonyl (33.6 mg, 0.088mmol), xantphos (10.24 mg, 0.018 mmol), and DMAP (130 mg, 1.061 mmol).The reaction mixture was heated to 80° C. for 35 min by microwaveirradiation. The reaction mixture was then heated to 80° C. for 20 minby microwave irradiation, and heated to 80° C. for a further 20 min bymicrowave irradiation. The reaction mixture was partitioned betweenethyl acetate (20 mL) and water (20 mL), the aqueous layer was extractedwith ethyl acetate (2×20 mL), and the organic layer was washed withwater (2×20 mL). This was passed through a hydrophobic frit and thesolvent removed under reduced pressure. The resulting orange solid wasdissolved in DMSO:methanol (1:1) and purified by MDAP (TFA). Theproduct-containing fractions were placed in a round-bottomed flask andthe solvent removed under reduced pressure. This was left to dry invacuo for 4 h to give1-(2-fluorobenzyl)-N5-(2-methoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(23 mg, 0.062 mmol, 17.41% yield) as a pale orange solid which waspurified by chiral preparative HPLC:

Analytical Method:

Approx 0.5 mg racemate was dissolved in 50% EtOH/Heptane (1 mL).Injection; 20 μL of the sample solution was injected onto the column(4.6 mmid×25 cm Chiralcel OJ-H Lot No. OJH0CE-RK007) eluting with 15%EtOH/heptane, at a rate of 1 mL/min and analysing with a wavelength of215 nm.

Preparative Method:

Approx 20 mg racemate was dissolved in EtOH (2 mL). Injection: 2 mL ofthe sample solution was injected onto the column (30 mm×25 cm ChiralcelOJ-H Lot No. OJH10027-01) eluting with 15% EtOH/heptane, at a rate of 30mL/min and analysing with a wavelength of 215 nm. Fractions from 23.5-26min were bulked and labelled peak 2. This gave the single enantiomer(Example 83) as a pale yellow solid (9 mg).

LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=374.1.

Example 86:1-(4-Fluorobenzyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(4-Fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.657 mmol) was taken up in DMF (5 mL) and HATU (275 mg,0.723 mmol) followed by DIPEA (0.230 mL, 1.315 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then(2-aminocyclopropyl)methanol (57.3 mg, 0.657 mmol, commerciallyavailable from, for example, Enamine) was added and the reaction wasallowed to stir for 1 h. The reaction mixture was concentrated undervacuum and purified by MDAP (High pH). The appropriate fractions werecombined and concentrated under vacuum to give the product (152 mg) as awhite solid.

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=374.1.

Example 87:N5-(2-Ethoxycyclopropyl)-1-(4-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(4-Fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.657 mmol) was taken up in DMF (5 mL) and HATU (275 mg,0.723 mmol) followed by DIPEA (0.230 mL, 1.315 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then2-ethoxycyclopropanamine (66.5 mg, 0.657 mmol, commercially availablefrom, for example, Enamine) was added and the reaction allowed to stirfor 1 h. The reaction mixture was concentrated under vacuum and purifiedby MDAP (High pH). The appropriate fractions were combined andconcentrated under vacuum to give the product (102 mg), as a yellowsolid.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=388.1.

Example 88:rac-N5-Cyclopropyl-N3-methyl-2-oxo-1-(1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide

5-(Methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylicacid (185 mg, 0.589 mmol), HATU (338 mg, 0.889 mmol), DIPEA (0.308 mL,1.766 mmol), cyclopropanamine (0.082 mL, 1.177 mmol) and DMF (2 mL) werestirred at rt under N₂ for 1 h. LiCl solution (20 mL) was added and thereaction mixture was partitioned between EtOAc (20 mL) and water (20mL), the aqueous phase was extracted with EtOAc (2×20 mL) and thecombined organic layers were dried over a hydrophobic frit andconcentrated to give 686 mg of a yellow oil. This was purified bychromatography on SiO₂ (Biotage SNAP 50 g cartridge, eluting with 0-100%EtOAc/cyclohexane). The appropriate fractions were concentrated to give376 mg of an orange oil. This was further purified by MDAP (TFA) and theappropriate fractions were concentrated to giverac-N5-cyclopropyl-N3-methyl-2-oxo-1-(1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide(61 mg, 0.155 mmol, 26.4% yield) a colourless oil.

LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=354.

Examples 89-94: Amide Array of1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

To a stock solution of1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (316 mg, 1 mmol) and HATU (380 mg) in DMF (5 mL) was added DIPEA(520 μL). The mixture was shaken and sonicated to aid dispersion. Themixture was aliquoted (0.55 mL) to a set of preweighed amines (as shownin the table below). These were capped and shaken and left to stand atrt for 18 h. The samples were purified by MDAP (High pH). The solventwas dried under a stream of nitrogen to give the required products.Example 93 was dissolved in DCM (0.5 mL) and treated with TFA (0.5 mL)and the solution left to stand in a capped vial at rt for 2 h. Thereaction mixture was evaporated and the residue dissolved in MeOH (0.5mL). The solution was applied to a MeOH-preconditioned 100 mg SCX-2cartridge which were then washed with MeOH (1 mL) followed by 2M ammoniain MeOH solution (1 mL). The basic washes were evaporated to dryness togive the final deprotected compound as the free base (as shown in thetable below).

Monomers

Reagent Ex Reagent Volume No. Reagent Name Structure MW Mass (g) (mL)mmol 89 3- fluorocyclo- butanamine hydrochloride

125.57 0.015 — 0.120 90 2- cyclopropyl- ethanamine

 85.15 0.010 — 0.120 91 rac-2- ethoxycyclo- propanamine

101.15 0.012 — 0.120 92 rac-(2- aminocyclopropyl) methanol

 87.12 0.010 — 0.120 93 tert-butyl (6- aminospiro[3.3] heptan-2-yl)carbamate

226.32 0.027 — 0.120 94 rac-(trans)-2- methylcyclo- propanamine

 71.12 0.009 — 0.120

Ex Mass Yield Rt no. Name Structure (mg) (%) [MH]+ (min) 89 N5-(3-fluorocyclobutyl)- 1-(3- methoxybenzyl)- N3-methyl-2-oxo- 1,2-dihydropyridine- 3,5-dicarboxamide

24.9 57.8 388 0.89 90 N5-(2- cyclopropylethyl)- 1-(3- methoxybenzyl)-N3-methyl-2-oxo- 1,2- dihydropyridine- 3,5-dicarboxamide

21.6 50.7 384 0.97 91 rac-N5-(2- ethoxycyclopropyl)- 1-(3-methoxybenzyl)- N3-methyl-2-oxo- 1,2- dihydropyridine- 3,5-dicarboxamide

20.1 45.3 400 0.89 92 rac-N5-(2- (hydroxymethyl) cyclopropyl)-1-(3-methoxybenzyl)- N3-methyl-2-oxo- 1,2- dihydropyridine- 3,5-dicarboxamide

6 14.0 386 0.74 93 N5-(6- Aminospiro[3.3] heptan-2-yl)-1-(3-methoxybenzyl)- N3-methyl-2-oxo- 1,2- dihydropyridine- 3,5-dicarboxamide

11.7 24.8 425 0.56 94 rac-1-(3- methoxybenzyl)- N3-methyl-N5-((trans)-2- methylcyclopropyl)- 2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

19.8 48.2 370 0.91

All LCMS were conducted using 2 min Formic method.

Example 95:1-(3-Acetylbenzyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-(3-acetylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (250 mg, 0.510 mmol), and HATU (291 mg, 0.765 mmol) in DMF (2041μL) stirred at rt was added cyclopropylamine (71.9 μL, 1.020 mmol) andDIPEA (178 μL, 1.020 mmol). And the reaction stirred for ˜18 h. Afurther portion of HATU (194 mg, 0.510 mmol) and the reaction stirredfor a further 1 h. The reaction mixture was poured onto water (45 mL)and the aqueous layer was extracted with ethyl acetate (3×20 mL) anddiethyl ether (2×20 mL). The combined organics were dried through ahydrophobic frit and evaporated in vacuo to yield the crude product asan orange oil (425 mg). The oil was loaded in dichloromethane/methanolonto a 25 g SNAP silica cartridge and purified via Biotage SP4 flashchromatography, eluting from 15-75% (3:1 ethylacetate:ethanol)/cyclohexane. The pure fractions were combined andevaporated in vacuo to yield the desired product (203 mg) as a cleargum. The product was taken up in ethyl acetate (50 mL) and washed withwater (10 mL) and brine (10 mL). The organic layer was dried through ahydrophobic frit and evaporated in vacuo toyield—1-(3-acetylbenzyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(148 mg, 0.383 mmol, 75% yield). The mixed fractions from the SP4chromatography were also combined and evaporated in vacuo to yield aclear gum which was taken up in ethyl acetate (50 mL) and washed withwater (10 mL) and brine (10 mL). The organic layer was dried through ahydrophobic frit and evaporated in vacuo to yieldfurther—1-(3-acetylbenzyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(38 mg, 0.095 mmol, 18.65% yield) as a clear glass.

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=368.2.

Example 96:rac-N5-Cyclopropyl-N3-methyl-2-oxo-1-(1-(o-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide

5-(Methylcarbamoyl)-6-oxo-1-(1-(o-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylicacid (190 mg, 0.604 mmol), HATU (355 mg, 0.934 mmol), DIPEA (0.32 mL,1.832 mmol), cyclopropanamine (0.084 mL, 1.209 mmol) and DMF (2 mL) werestirred at rt under N₂ for 2 h. The reaction mixture was washed withLiCl solution (20 mL) and partitioned between EtOAc (20 mL) and water(20 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and thecombined organic layers were dried over a hydrophobic frit andconcentrated to give 449 mg of a red oil. This was purified bychromatography on SiO₂ (Biotage SNAP 50 g cartridge, eluting with 0-100%EtOAc/cyclohexane). The appropriate fractions were concentrated to giverac-N5-cyclopropyl-N3-methyl-2-oxo-1-(1-(o-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide(183 mg, 0.466 mmol, 77% yield).

LCMS (2 min Formic): Rt=0.93 min, [MH]⁺=354.

Example 97:1-(4-Fluoro-3-methylbenzyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(4-Fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.628 mmol) was taken up in DMF (5 mL) and HATU (263 mg,0.691 mmol) followed by DIPEA (0.219 mL, 1.257 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then(2-aminocyclopropyl)methanol (54.7 mg, 0.628 mmol, commerciallyavailable from, for example, Enamine) was added and the reaction allowedto stir for 1 h. The reaction mixture was concentrated under vacuum andpurified by MDAP (High pH). The appropriate fractions were combined andconcentrated under vacuum to give the crude product. This was furtherpurified by MDAP (High pH). The product containing fractions werecombined to give the product (140 mg) as a white solid.

LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=388.1.

Example 98:N5-(2-Ethoxycyclopropyl-1-(4-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(4-Fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.628 mmol) was taken up in DMF (5 mL) and HATU (263 mg,0.691 mmol), followed by DIPEA (0.219 mL, 1.257 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then2-ethoxycyclopropanamine (63.6 mg, 0.628 mmol, commercially availablefrom, for example, Enamine) was added and the reaction allowed to stirfor 1 h. The reaction mixture was concentrated under vacuum and purifiedby MDAP (High pH). The appropriate fractions were combined andconcentrated under vacuum to give the desired product (141 mg, 0.351mmol, 55.9% yield) as a white solid.

LCMS (2 min Formic): Rt=0.98 min, [MH]⁺=402.2.

Example 99:N5-Cyclopropyl-N3-methyl-2-oxo-1-((1,2,3,4-tetrahydroquinolin-8-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of5-(methylcarbamoyl)-6-oxo-1-((1,2,3,4-tetrahydroquinolin-8-yl)methyl)-1,6-dihydropyridine-3-carboxylicacid (132 mg, 0.255 mmol), and HATU (146 mg, 0.383 mmol) in DMF (1 mL)(stirred at rt) was added cyclopropylamine (54.0 μL, 0.766 mmol) andDIPEA (89 μL, 0.510 mmol). The reaction was stirred for 16 h. A furtherportion of HATU (48.5 mg, 0.128 mmol) was added and the reaction wascontinued for 17 h. A further portion of HATU (48.5 mg, 0.128 mmol) wasadded and the reaction was stirred for 20.5 h. The reaction mixture waspoured onto saturated aqueous lithium chloride (15 mL) and the aqueouswas extracted with ethyl acetate (4×10 mL). The combined organics werewashed with brine, dried through a hydrophobic frit and evaporated invacuo to yield the crude product as an orange oil (311 mg). The samplewas loaded in dichloromethane onto a 25 g SNAP cartridge and purifiedvia Biotage SP4 flash chromatography, eluting from 10-50% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo to yield a yellow solid (99 mg). The sample wasdissolved in 1:1 MeOH:DMSO (2×1 mL) and was purified by MDAP (High pH).The solvent was evaporated in vacuo to giveN5-cyclopropyl-N3-methyl-2-oxo-1-((1,2,3,4-tetrahydroquinolin-8-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(47 mg, 0.117 mmol, 46.0% yield) as a yellow solid.

LCMS (2 min Formic): Rt=0.86 min, [MH]⁺=381.2.

Example 100:(+/−)-1-(3-Fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

DIPEA (0.276 mL, 1.578 mmol) was added to a suspension of1-(3-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.526 mmol), (+/−)-(trans)-2-methylcyclopropanamine (74.8mg, 1.052 mmol, commercially available from, for example, Fluorochem),and HATU (300 mg, 0.789 mmol) in DMF (4 mL). The reaction mixture wasstirred at rt for 4 h, after which further(+/−)-(trans)-2-methylcyclopropanamine (74.8 mg, 1.052 mmol), HATU (300mg, 0.789 mmol), and DIPEA (0.276 mL, 1.578 mmol) were added. Thereaction mixture was left to stand in solution overnight. The resultingorange oil was dissolved in 1:1 DMSO:methanol and purified by MDAP(TFA). The product-containing fractions were combined and the solventremoved under reduced pressure. The product was left to dry in vacuo for2 h to give(+/−)-1-(3-fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(72 mg, 0.201 mmol, 38.3% yield) as a dark orange solid.

LCMS (2 min Formic): Rt=0.93 min, [MH]⁺=358.2.

Example 101:1-Benzyl-N3-methyl-N5-((1R,2R)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideand Example 102:1-Benzyl-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-(trans)-2-Methylcyclopropanamine (149 mg, 2.096 mmol, commerciallyavailable from, for example, Fluorochem) was added to a suspension of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(300 mg, 1.048 mmol), HATU (598 mg, 1.572 mmol), and DIPEA (0.549 mL,3.14 mmol) in DMF (6 mL). The reaction mixture was stirred for 1 h andleft to react over the weekend. Further(+/−)-(trans)-2-methylcyclopropanamine (149 mg, 2.096 mmol), HATU (598mg, 1.572 mmol), and DIPEA (0.549 mL, 3.14 mmol) were added and thereaction was stirred for 1 h. The reaction mixture was partitionedbetween ethyl acetate and water and the aqueous layer was extracted with2× ethyl acetate. The organic layer was washed with 2× water and 1×brine and the solvent was removed under reduced pressure. The resultingorange oil was dissolved in DCM and loaded onto a 25 g Biotage SNAPsilica column which was eluted with cyclohexane:ethyl acetate (0-80%).The product-containing fractions were combined and the solvent removedunder reduced pressure. The product was left to dry in vacuo for 2 days.The product was further purified by MDAP (Formic) and the solvent wasremoved under reduced pressure. The clean product was left to dry invacuo for 1 day to give(+/−)-1-benzyl-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(70 mg, 0.206 mmol, 19.68% yield) as a pale yellow solid. The racemicmixture was purified by chiral HPLC:

Analytical Method:

Approx 0.5 mg racemate was dissolved in 50% EtOH/Heptane (1 mL).Injection; 20 μL of the sample solution was injected onto the column(4.6 mm id×25 cm Chiralcel OJ-H Lot No. OJH0CE-QL055) eluting with 5%EtOH (+0.2% isopropylamine)/heptane, at a rate of 1 mL/min and analysingwith a wavelength of 215 nm.

Preparative Method:

Approx. 70 mg racemate was dissolved in EtOH (0.5 mL). Injection: 0.5 mLof the sample solution was injected onto the column (30 mm×25 cmChiralcel OJ-H Lot No. OJH10027-01) eluting with 5% EtOH (+0.2%isopropylamine)/heptane (+0.2% isopropylamine), at a rate of 30 mL/minand analysing with a wavelength of 215 nm.

Fractions from 34-41 min were bulked and labelled peak 1.

This gave the single enantiomer 1 (example 101) as a white solid (20mg).

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=340.1.

Fractions from 44-54 min were bulked and labelled peak 2.

This gave the single enantiomer 2 (example 102) as a white solid (23mg).

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=340.1.

¹H NMR (400 MHz, CHCl₃-d) δ ppm 9.52 (br. s., 1H) 8.66 (d, J=2.7 Hz, 1H)8.46 (d, J=2.7 Hz, 1H) 7.29-7.41 (m, 5H) 6.39 (br. s., 1H) 5.25 (s, 2H)2.99 (d, J=4.9 Hz, 3H) 2.55 (dd, J=7.1, 3.7 Hz, 1H) 1.14 (d, J=6.1 Hz,3H) 0.97 (app. dquind, J=9.2, 6.0, 6.0, 6.0, 6.0, 3.3 Hz, 1H) 0.77 (ddd,J=9.3, 5.5, 3.8 Hz, 1H) 0.61-0.67 (m, 1H)

Alternative Process for the Preparation of Example 102

To a suspension of1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid(1.7 g) and (1S,2S)-2-methylcyclopropanamine, hydrochloride (0.639 g, 1eq) in Dichloromethane (25.5 mL) was added triethylamine (2.48 mL, 3eq). Propyl phosphonic anhydride (50% in ethyl acetate, 3.53 mL, 1.1 eq)was added dropwise with cooling to keep the temperature below 20° C. Themixture was then stirred for 1 h at rt. Once complete by HPLC, saturatedsodium bicarbonate solution (10 mL) was added. After stirring for 10min, the layers were separated and the aqueous phase was back extractedwith DCM (5 vol). The combined DCM layers were washed with water (2×10mL). The DCM layer was then dried over sodium sulphate and pumpedthrough a 2 lenticle R55SP zeta carbon cuno cartridge at 120 mL/min. Thecartridge was washed with DCM (17 mL) and the combined DCM solution wasconcentrated to dryness to give a yellow foam. The foam was dissolved inethyl acetate (34 mL) after stirring for 30 min solid precipitated fromsolution and the slurry was cooled to 5±3° C. and aged for at least 2 h.The solid was then filtered off under vacuum and washed with cold ethylacetate (3.4 mL). The product was then dried in vacuo at 40° C. toconstant probe temperature. Yield: 52.6%.

Example 103:1-(4-Fluoro-3-methylbenzyl)-N3-methyl-N5-(2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(4-Fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.628 mmol) was taken up in DMF (5 mL) and HATU (263 mg,0.691 mmol) followed by DIPEA (0.219 mL, 1.257 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then2-methylcyclopropanamine (44.7 mg, 0.628 mmol, commercially availablefrom, for example, Enamine) was added and the reaction allowed to stirfor 1 h. The reaction mixture was concentrated under vacuum and purifiedby MDAP (High pH). The appropriate fractions were combined andconcentrated under vacuum to give the desired product (166 mg, 0.447mmol, 71.1% yield) as a white solid.

LCMS (2 min Formic): Rt=1.00 min, [MH]⁺=372.1.

Example 104:N5-Cyclopropyl-1-(3-(2-(dimethylamino)ethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2-Bromo-N,N-dimethylethanamine (23 mg, 0.151 mmol, commerciallyavailable from, for example, City Chemical LLC) was added to asuspension ofN5-cyclopropyl-1-(3-hydroxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(46 mg, 0.135 mmol) and sodium hydride (11 mg, 60% dispersion in mineraloil, 0.275 mmol) in DMF (1 mL) at rt under N₂. After 1.5 h furtherportions of sodium hydride (10 mg, 60% dispersion in mineral oil, 0.25mmol) and 2-bromo-N,N-dimethylethanamine (40 mg, 0.263 mmol) were added.After stirring for another 1 h, further portions of2-bromo-N,N-dimethylethanamine (102 mg, 0.674 mmol) and sodium hydride(20 mg, 60% dispersion in mineral oil, 0.50 mmol) were added and thereaction mixture was stirred overnight. The reaction was quenched withwater (20 mL), extracted with EtOAc (3×20 mL) and the combined organiclayers dried over a hydrophobic frit and concentrated to give 193 mg ofan of white solid. This was purified by chromatography on SiO₂ (BiotageSNAP 25 g cartridge, eluting with 0-50% (25% EtOH in EtOAc)/EtOAc)followed by 20% 2M NH₃ in MeOH in DCM and the appropriate fractions werecollected to giveN5-cyclopropyl-1-(3-(2-(dimethylamino)ethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(6 mg, 0.012 mmol, 9.18% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.46 min, [MH]+=413.

Example 105:N5-(((+/−)-trans)-2-Ethoxycyclopropyl)-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

DIPEA (0.276 mL, 1.578 mmol) was added to a suspension of1-(3-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.526 mmol), 2-ethoxycyclopropanamine, HCl salt (106 mg,1.052 mmol, commercially available from, for example, Enamine), and HATU(300 mg, 0.789 mmol) in DMF (4 mL). The reaction mixture was stirred atrt for 90 min. The reaction mixture was partitioned between ethylacetate (20 mL) and water (20 mL) and the organic layer washed withwater (2×20 mL) and brine (20 mL). This was passed through a hydrophobicfrit and the solvent removed under reduced pressure. The resultingorange oil was dissolved in DCM and purified by flash chromatographyusing a 25 g Biotage SNAP silica column and a gradient of 0-100% ethylacetate/cyclohexane. The fractions were found to be impure so theproduct-containing fractions were combined, the solvent removed underreduced pressure, and the resulting orange oil dissolved inDMSO/methanol (1:1). This was then purified by MDAP (TFA)—theproduct-containing fractions were combined and the solvent removed underreduced pressure. The product was left to dry in vacuo for 2 days togiveN5-(2-ethoxycyclopropyl)-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(200 mg, 0.516 mmol, 98% yield) as a pale orange solid, as a mixture ofdiastereomers, these were resolved by achiral HPLC:

The sample was dissolved in 9 mL of DMSO. 3000 μL injections were madeonto a CSH C18 150×30 mm, 5 μm. column using the chromatographicconditions listed. Solvent A: 0.1% v/v solution of Formic Acid in Water,solvent B: 0.1% v/v solution of Formic Acid in Acetonitrile, flow Rate:40 mL/min. Gradient: as below:

Time/min % B % A 0 20 80 3.5 20 80 25 40 60 32 40 60 35 99 1

Fractionation was determined by mixture of diode array & mass specsignal: UV detection: a summed signal from wavelengths 210 nm to 350 nm.MS: Waters SQ, Ionisation mode: Alt. Pos./Neg. Electrospray, Scan Range:100 to 1000 AMU, Scan Time: 0.5 s, Inter scan Delay: 0.2 s. The flow andgradient was provided by a two pumps with a reduced flow passing throughthe injector during injection. The residual flow is introduced at thehead of the column so the overall flow remains constant. Thefractionation collected samples into multiple vessels and the suitablefractions were combined and dried using a Biotage V10 evaporator. Thisgave the trans-diastereomer (Example 105) as a white solid (106 mg).

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=388.1.

Example 106:(+/−)-1-((1H-Indol-4-yl)methyl)-N5-((trans)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (25 mg, 0.077 mmol), and HATU (35.1 mg, 0.092 mmol) in DMF (500 μL)stirred at rt was added (+/−)-(trans)-2-ethylcyclopropanamine,hydrochloride (18.69 mg, 0.154 mmol, commercially available from, forexample, Enamine) and DIPEA (26.8 μL, 0.154 mmol) and the reactionstirred for 30 min. The reaction mixture was diluted with DMSO (0.5 mL)and purified by MDAP (High pH). The solvent was evaporated in vacuo toyield the pure product(+/−)-1-((1H-indol-4-yl)methyl)-N5-((trans)-2-ethylcyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(15 mg, 0.036 mmol, 47.2% yield) as an off white solid.

LCMS (2 min Formic): Rt=0.93 min, [MH]⁺=393.2.

Examples 107-112: Amide Array of1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

To a stock solution of1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (337 mg, 0.97 mmol) and HATU (374 mg) in DMF (5.5 mL) was addedDIPEA (550 μL). The solution was shaken and sonicated to aid dispersionand aliquoted (0.55 mL) to a set of preweighed amines (as shown in tablebelow). Additional DIPEA (55 μL) was added to example 107 reactionmixture to compensate for HCl salt of the amine monomer. After 18 h atrt, the samples were injected as is and purified by MDAP (High pH). Thesolvent was dried under a stream of nitrogen to give the requiredproducts. Example 111 was dissolved in DCM (0.5 mL) and treated with TFA(0.5 mL) and the solution left to stand in a capped vial at rt for 2 h.The reaction mixture was evaporated and example 111 was dissolved inMeOH (0.5 mL). The solution was applied to a MeOH-preconditioned 100 mgSCX-2 cartridge which was then washed with MeOH (1 mL) followed by 2 Mammonia in MeOH solution (1 mL). The basic washes were evaporated todryness to give the final deprotected compound as the free base (asshown in table below). Example 111 was re-purified by MDAP (High pH).The solvent was dried under a stream of nitrogen to give the requiredproduct.

Monomers

Reagent Ex Reagent Volume No. Reagent Name Structure MW Mass (g) (mL)mmol 107 3- fluorocyclo- butanamine hydrochloride

125.57 0.014 — 0.120 108 2- cyclopropyl- ethanamine

 85.15 0.010 — 0.114 109 rac-2- ethoxycyclo- propanamine

101.15 0.012 — 0.114 110 rac-(2- aminocyclo- propyl)methanol

 87.12 0.010 — 0.114 111 tert-butyl (6- aminospiro[3.3] heptan-2-yl)carbamate

226.32 0.026 — 0.114 112 rac-(trans)-2- methylcyclo- propanamine

 71.12 0.008 — 0.114

EXAMPLES

Ex Mass Yield Rt no. Name Structure (mg) (%) [MH]+ (min) 107 N5-(3-fluorocyclo- butyl)-1-(3-(2- hydroxyethoxy) benzyl)-N3- methyl-2-oxo-1,2- dihydropyridine- 3,5- dicarboxamide

18.7 45.0 418 0.74 108 N5-(2- cyclopropyl- ethyl)-1-(3-(2-hydroxyethoxy) benzyl)-N3- methyl-2-oxo- 1,2- dihydropyridine- 3,5-dicarboxamide

19.5 47.4 414 0.82 109 rac-N5-(2- ethoxycyclo- propyl)-1-(3-(2-hydroxyethoxy) benzyl)-N3- methyl-2-oxo- 1,2- dihydropyridine- 3,5-dicarboxamide

17.3 40.5 430 0.74 110 rac-1-(3-(2- hydroxyethoxy) benzyl)-N5-(2-(hydroxymethyl) cyclopropyl)- N3-methyl-2- oxo-1,2- dihydropyridine-3,5- dicarboxamide

12.6 30.5 416 0.62 111 N5-(6- Aminospiro[3.3] heptan-2-yl)-1- (3-(2-hydroxyethoxy) benzyl)-N3- methyl-2-oxo- 1,2- dihydropyridine- 3,5-dicarboxamide

 5.9 13.1 455 0.47 112 rac-1-(3-(2- hydroxyethoxy) benzyl)-N3-methyl-N5- ((trans)-2- methylcyclo- propyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

 8.4 21.1 400 0.75

All LCMS were conducted using 2 min Formic method.

Example 113:(R*)—N5-Cyclopropyl-N3-methyl-2-oxo-1-(1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide—Enantiomer1

rac-N5-Cyclopropyl-N3-methyl-2-oxo-1-(1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide(for example, Example 88, 117 mg) was dissolved in EtOH (3 mL) andpurified by chiral chromatography:

Analytical Method:

Approx 0.5 mg of racemate was dissolved in 50% EtOH/Heptane (1 mL). 20μL was injected on the column (Column: 4.6 mmid×25 cm Chiralpak AD-H,Lot No. ADH0CE-PC014). This was eluted with 25% EtOH/Heptane, flowrate=1.0 mL/min, detection wavelength=215 nm, 4. Ref 550, 100

Preparative Method:

Approx 117 mg of racemate was dissolved in 3 mL EtOH. Injection; 1 mL ofthe solution was injected onto the column (Column: 30 mm×25 cm ChiralpakAD-H, Lot No. ADH12143-01). This was eluted with 25% EtOH/Heptane, flowrate=30 mL/min, detection wavelength=215 nm, 4. Ref 550, 100. Totalnumber of injections: 3. Fractions from 10.5-13.5 min were bulked andlabelled peak 1. Fractions from 15.5-24 min were bulked and labelledpeak 2. The combined fractions for peak 1 were evaporated in vacuo togive pure enantiomer 1 as a white solid (51 mg),

LCMS (2 min Formic): Rt=0.96 min, [MH]+=354.

Example 115:N5-(2-Ethoxycyclopropyl)-1-(2-fluoro-5-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(4-Fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.628 mmol) was taken up in DMF (5 mL) and HATU (263 mg,0.691 mmol) followed by DIPEA (0.219 mL, 1.257 mmol). The reactionmixture was allowed to stir for 5 min, then 2-ethoxycyclopropanamine(47.7 mg, 0.471 mmol, commercially available from, for example, Enamine)was added and the reaction allowed to stir for 1 h. The reaction mixturewas concentrated under vacuum and purified by MDAP (High pH). Theappropriate fractions were combined and concentrated under vacuum togive the desired product (100 mg, 0.249 mmol, 52.9% yield) as a whitesolid.

LCMS (2 min Formic): Rt=0.97 min, [MH]⁺=402.2.

Examples 116-118 and 130: Amide Array of1-(2-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Monomers

Reagent Reagent Volume Ex No. Reagent Name Structure MW Mass (g) (mL)mmol 116 2- cyclopropylethanamine

 85.15 0.0102 — 0.120 117 2- (ethoxymethyl) cyclopropanamine

101.15 0.0121 — 0.120 118 3- fluorocyclobutanamine hydrochloride

125.57 0.0107 — 0.085 130 tert-butyl (6- aminospiro[3.3] heptan-2-yl)carbamate

226.32 0.0272 — 0.120

To a stock solution of1-(2-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (350 mg, 1.1 mmol) dissolved in DMF (5.5 mL) was added HATU (502mg, 2.13 mmol) and DIPEA (570 μL, 3.3 mmol). The mixture was sonicatedto aid dispersion and further DMF (5.5 mL) was added. An aliquot (1.0mL) of this mixture was added to the appropriate amine (0.12 mmol) inDMF (0.3 mL) in a vial which was subsequently sealed, sonicated and leftto stand at rt for 3 h. The samples were reduced to 1 mL, then injectedas is and purified by MDAP (High pH). The solvent was removed using aplate dryer to give the required products as shown in the table.

DCM (0.5 mL) and TFA (0.5 mL) were added to the product derived from theamine monomer used to prepare example 130 and the vial was capped andleft to stand at rt for 2 h. The solvent was removed using a platedryer. The residue was redissolved in MeOH (0.5 mL) and applied to thetop of a SCX-2 SPE cartridge (1 g, preconditioned with MeOH (1 mL)). Thecartridge was eluted with further MeOH (1 mL) followed by 2M NH₃/MeOH (1mL). The solvent was evaporated from the sample under a stream ofnitrogen. The residue was dissolved in DCM (1 mL) and applied to aaminopropyl cartridge (100 mg), (preconditioned with CHCl₃), and thiswas eluted with further CHCl₃ (1 mL) and concentrated to provide thedesired example 130.

EXAMPLES

Ex Mass Yield Rt No. Name Structure (mg) (%) [MH]⁺ (min)* 116 N5-(2-cyclopropylethyl)-1- (2-fluoro-3- methylbenzyl)-N3- methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

22.5 53 386 1.05 117 N5-(2- ethoxycyclopropyl)- 1-(2-fluoro-3-methylbenzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

26.6 50 402 0.96 118 1-(2-fluoro-3- methylbenzyl)-N5- (3-fluorocyclobutyl)- N3-methyl-2-oxo- 1,2-dihydropyridine-3,5-dicarboxamide

25.7 59 389 0.97 130 N5-(6- aminospiro[3.3] heptan-2-yl)-1-(2- fluoro-3-methylbenzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

 3.4 6.0 346 0.90

Example 119:1-(4-Fluorobenzyl)-N5-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide—Enantiomer1 and Example 120:1-(4-Fluorobenzyl)-N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide—Enantiomer2

1-(4-Fluorobenzyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(for example, Example 86, 145 mg) was dissolved in EtOH (9 mL) andpurified by chiral chromatography:

Analytical Method:

Approx 0.5 mg racemate was dissolved in 50% EtOH/Heptane (1 mL). 20 μLof this was injected on the column (Column 4.6 mmid×25 cm ChiralpakAD-H, Lot No. ADH0CE-PC014) and eluted with 60% EtOH/Heptane, flowrate=1.0 mL/min, detection wavelength 215 nm, 4. Ref 550, 100.

Preparative Method:

Approx 145 mg racemate was dissolved in 9 mL EtOH+heat. Injection; 3 mLof the solution was injected onto the column (Column: 30 mm×25 cmChiralpak AD-H, Lot No. ADH12143-01) and eluted with 60% EtOH/Heptane,flow rate=25 mL/min, detection wavelength 215 nm, 4. Ref 550,100. Totalnumber of injections=3. Fractions from 14-19 min were bulked andlabelled peak 1. Fractions from 22-31 min were bulked and labelled peak2. The bulked fractions were vac'ed down using a rotary evaporator andthen transferred to a weighed flask for final analysis as described bythe analytical method above. The combined fractions from peak 1 wereevaporated in vacuo to give pure enantiomer 1 as a colourless solid (72mg).

HPLC-UV: RT˜11.0 minutes, >99.5% isomeric purity by area HPLC @ 215 nm.

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=374.1

The combined fractions from peak 2 were evaporated in vacuo to give pureenantiomer 2 as a colourless solid (65 mg).

HPLC-UV: RT˜19.0 minutes, 98.3% isomeric purity by area HPLC @ 215 nm.

LCMS (2 min Formic): Rt=0.76 min, [MH]⁺=374.2.

Example 121:1-(4-Fluorobenzyl)-N3-methyl-N5-((1R,2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide—Enantiomer1 and Example 122:1-(4-Fluorobenzyl)-N3-methyl-N5-((1S*2S*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide—Enantiomer2

(+/−)-1-(4-Fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(for example Example 82, 90 mg) was dissolved in EtOH (2 mL) andpurified by chiral chromatography:

Analytical Method:

Approx 0.5 mg racemate was dissolved in 50% EtOH/Heptane (1 mL). 20 μLof the sample was injected on the column (Column: 4.6 mmid×25 cmChiralcel OJ-H, Lot No. OJH0CE-QL055) and this was eluted with 5% EtOH(+0.2% isopropylamine)/Heptane, flow rate=1.0 mL/min, detectionwavelength=215 nm, 4. Ref 550, 100.

Preparative Method:

Approx 90 mg of racemate was dissolved in 2 mL EtOH+heat. Injection: 1mL of the solution was injected onto the column (Column: 30 mm×25 cmChiralcel OJ-H, Lot No. OJH10027-01). This was eluted with 5% EtOH(+0.2% isopropylamine)/Heptane (+0.2% isopropylamine), flow rate=30mL/min, detection wavelength=215 nm, 4. Ref 550, 100. Total number ofinjections=3. Fractions from 31-38 min were bulked and labelled peak 1.Fractions from 38-43 min were bulked and labelled mix. Fractions from43-54 min were bulked and labelled peak 2. The mix fractions werebulked, vac'ed down and reprocessed using the prep method above. Thebulked fractions were vac'ed down using a rotary evaporator and thentransferred to a weighed flask for final analysis as described by theanalytical method above. The combined fractions for peak 1 wereevaporated in vacuo to give pure enantiomer 1 as a colourless solid (44mg).

HPLC-UV: RT˜30 minutes, >99.5% isomeric purity by area HPLC @ 215 nm.

LCMS (2 min Formic): Rt=0.92 min, [MH]⁺=358.2

The combined fractions for peak 2 were evaporated in vacuo to give pureenantiomer 2 as a colourless solid (43 mg).

HPLC-UV: RT˜40 minutes, 97% isomeric purity by area HPLC @ 215 nm.

LCMS (2 min Formic): Rt=0.92 min, [MH]⁺=358.1.

Example 123:N5-((1R*,2R*)-2-ethoxycyclopropyl)-1-(4-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide—Enantiomer1 and Example 124:N5-((1S,2S*)-2-ethoxycyclopropyl)-1-(4-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide—Enantiomer1

N5-(2-Ethoxycyclopropyl)-1-(4-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(for example, Example 87, 98 mg) was dissolved in EtOH (2 mL) andpurified by chiral chromatography:

Analytical Method:

Approx 0.5 mg racemate was dissolved in 50% EtOH/Heptane (1 mL). 20 μLof the sample was injected on the column (Column: 4.6 mmid×25 cmChiralcel OJ-H, Lot No. OJH0CE-QL055). This was eluted with 40%EtOH/Heptane, flow rate=1.0 mL/min, detection wavelength=215 nm, 4. Ref550, 100

Preparative Method:

Approx 98 mg racemate was dissolved in 2 mL EtOH+heat. Injection: 2 mLof the solution was injected onto the column (Column: 30 mm×25 cmChiralcel OJ-H, Lot No. OJH10027-01). This was eluted with 40%EtOH/Heptane, flow rate=30 mL/min, detection wavelength=215 nm, 4. Ref550, 100. Total number of injections=1. Fractions from 7.5-11 min werebulked and labelled peak 1. Fractions from 13.5-21 min were bulked andlabelled peak 2. The bulked fractions were vac'ed down using a rotaryevaporator and then transferred to a weighed flask for final analysis asdescribed by the analytical method above. The combined fractions frompeak 1 were evaporated in vacuo to give pure enantiomer 1 as acolourless solid (45 mg).

HPLC-UV: RT˜7.5 minutes, >99.5% isomeric purity by area HPLC @ 215 nm.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=388.2

The combined fractions for peak 2 were evaporated in vacuo to give pureenantiomer 2 as a colourless solid (44 mg).

HPLC-UV: RT˜13.5 minutes, >99.5% isomeric purity by area HPLC @ 215 nm.

LCMS (2 min Formic): Rt=0.92 min, [MH]⁺=358.1.

Example 125:N5-((1R*,2R*)-2-Ethoxycyclopropyl)-1-(4-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide—Enantiomer1 and Example 126:N5-((1S*,2S*)-2-Ethoxycyclopropyl)-1-(4-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide—Enantiomer2

N5-(2-Ethoxycyclopropyl)-1-(4-fluoro-3-methylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(for example, Example 98, 144 mg) was dissolved in EtOH (2 mL) andpurified by chiral chromatography:

Analytical Method:

Approx 0.5 mg racemate was dissolved in 50% EtOH/Heptane (1 mL). 20 μLof the sample was injected on the column (Column: 4.6 mm id×25 cmChiralcel OJ-H, Lot No. OJH0CE-QL055). This was eluted with 25%EtOH/Heptane, flow rate=1.0 mL/min, detection wavelength=215 nm, 4. Ref550, 100

Preparative Method:

Approx 144 mg racemate was dissolved in 2 mL EtOH+heat. Injection; 1 mLof the solution was injected onto the column (Column: 30 mm×25 cmChiralcel OJ-H, Lot No. OJH10027-01). This was eluted with 25%EtOH/Heptane, flow rate=30 mL/min, detection wavelength=215 nm, 4. Ref550, 100. Total number of injections=2. Fractions from 8-9.5 min werebulked and labelled peak 1. Fractions from 12-17 min were bulked andlabelled peak 2. The bulked fractions were vac'ed down using a rotaryevaporator and then transferred to a weighed flask for final analysis asdescribed by the analytical method above. The combined fractions forpeak 1 were evaporated in vacuo to give pure enantiomer 1 as acolourless solid (56 mg).

HPLC-UV: RT˜7.0 minutes, >99.5% isomeric purity by area HPLC @ 215 nm.

LCMS (2 min Formic): Rt=0.98 min, [MH]⁺=402.2

The combined fractions for peak 2 were evaporated in vacuo to give pureenantiomer 2 as a colourless solid (66 mg).

HPLC-UV: RT˜11.5 minutes, >99.5% isomeric purity by area HPLC @ 215 nm.

LCMS (2 min Formic): Rt=0.99 min, [MH]⁺=402.3.

Example 127:N5-((1R*,2R*)-2-ethoxycyclopropyl)-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideand Example 128:N5-((1S*,2S*)-2-ethoxycyclopropyl)-1-(3-fluorobenzyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-N5-((trans)-2-Ethoxycyclopropyl)-1-(3-fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(for example, example 105, ˜100 mg) was submitted for chiral separation:

Analytical Method:

Approx 0.5 mg diastereomer was dissolved in 50% EtOH/heptane (1 mL).Injection: 20 μL of the sample solution was injected onto column (4.6 mmid×25 cm Chiralcel OJ-H Lot No. OJH0CE-QL055) eluting with 20%EtOH/heptane, at a rate of 1 mL/min and analysing with a wavelength of215 nm.

Preparative Method:

Approx 100 mg diastereomer dissolved in EtOH (1 mL)+heat. Injection: 1mL of the sample solution was injected onto the column (30 mm×25 cmChiralcel OJ-H Lot No. OJH10027-01) eluting with 20% EtOH/heptane at arate of 30 mL/min and analysing with a wavelength of 215 nm. Fractionsfrom 10-14 min were bulked and labelled peak 1. Fractions from 15.5-21min were bulked and labelled peak 2.

Peak 1: This gave the single enantiomer (Example 127) as a white solid(40 mg).

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=388.2.

Peak 2: This gave the single enantiomer (Example 128) as a white solid(40 mg).

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=388.2.

Example 129:N5-Cyclopropyl-N3-methyl-2-oxo-1-((1,2,3,4-tetrahydroisoquinolin-5-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide

tert-Butyl5-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(5 mg, 10.40 μmol) and TFA (0.1 mL, 1298 μmol) were stirred at rt in DCM(0.4 mL) for 30 min. The reaction mixture was concentrated and loadedonto a 500 mg SCX cartridge (pre-conditioned with MeOH) and eluted withMeOH (5 mL) followed by 2M NH₃ in MeOH (5 mL). The ammonia fractionscontaining product were combined and concentrated to giveN5-cyclopropyl-N3-methyl-2-oxo-1-((1,2,3,4-tetrahydroisoquinolin-5-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(4 mg, 9.46 μmol, 91% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.42 min, [MH]+=381.

Example 131:1-(2-Fluoro-5-methylbenzyl)-N5-(2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(2-Fluoro-5-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (120 mg, 0.377 mmol) was taken up in DMF (3 mL) and HATU (158 mg,0.415 mmol) followed by DIPEA (0.132 mL, 0.754 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then(2-aminocyclopropyl)methanol (32.8 mg, 0.377 mmol, commerciallyavailable from, for example, Enamine) was added and the reaction allowedto stir for 1 h. The reaction mixture was concentrated under vacuum andpurified by MDAP (High pH). The appropriate fractions were combined andconcentrated under vacuum to give the title compound (90 mg, 0.232 mmol,61.6% yield) as an orange-white solid.

LCMS (2 min Formic): Rt=0.81 min, [MH]⁺=388.2.

Example 132:(+/−)-N5-((trans)-2-(Hydroxymethyl)cyclopropyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(3-Methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.632 mmol) was taken up in DMF (3 mL) and HATU (264 mg,0.696 mmol) followed by DIPEA (0.221 mL, 1.265 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then(2-aminocyclopropyl)methanol (55.1 mg, 0.632 mmol, commerciallyavailable from, for example, Enamine) was added and the reaction allowedto stir for 1 h. The reaction mixture was concentrated under vacuum andpurified by MDAP (High pH). The appropriate fractions were combined andconcentrated under vacuum to give the title compound (161 mg, 0.418mmol, 66.1% yield) as a white solid.

LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=386.2.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.35 (br. q, J=4.5, 4.5, 4.5 Hz, 1H)8.80 (d, J=2.7 Hz, 1H) 8.69 (d, J=2.7 Hz, 1H) 8.56 (br. d, J=4.2 Hz, 1H)7.27 (t, J=7.8 Hz, 1H) 6.82-6.92 (m, 3H) 5.25 (s, 2H) 4.48 (t, J=5.5 Hz,1H) 3.73 (s, 3H) 3.30-3.42 (m, 2H) 2.82 (d, J=4.9 Hz, 3H) 2.71 (m,J=7.3, 3.4 Hz, 1H) 1.22 (dqd, J=9.1, 6.1, 6.1, 6.1, 3.4 Hz, 1H)0.64-0.72 (m, 2H).

Example 133:1-(2-Fluorobenzyl)-N3-methyl-N5-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideand Example 134:1-(2-Fluorobenzyl)-N3-methyl-N5-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-1-(2-Fluorobenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(for example, example 61, ˜30 mg) was submitted for chiral separation:

Analytical Method:

Approx 0.5 mg racemate dissolved in 50% EtOH/heptane (1 mL). Injection;20 μL of the sample solution was injected onto a column (4.6 mm id×25 cmChiralpak IA Lot No. IA00CE-MC024) eluting with 10% EtOH(+0.2%isopropylamine)/heptane, at a rate of 1 mL/min and analysing with awavelength of 215 nm.

Preparative Method:

Approx 30 mg racemate dissolved in EtOH (2 mL). Injection: 0.5 mL of thesample solution was injected onto a column (2 cm×25 cm Chiralpak IA (5μm) Lot No. IA00CJ-KF008) eluting with 10% EtOH (+0.2%isopropylamine)/heptane (+0.2% isopropylamine), at a rate of 20 mL/minand analysing with a wavelength of 215 nm. Fractions from 34-37 min werebulked and labelled peak 1; fractions from 37-40 min were bulked andlabelled mix. Fractions from 40-50 min were bulked and labelled peak 2.The bulked mix fractions were vac'ed down and reprocessed using the theprep method above.

Peak 1: This gave the single enantiomer (Example 133) as a white solid(11 mg).

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=358.2.

Peak 2: This gave the single enantiomer (Example 134) as a white solid(10 mg).

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=358.2.

Examples 135-138: Amide Array of1-((1H-Indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Monomers

Reagent Reagent Volume Ex No. Reagent Name Structure MW Mass (g) (mL)mmol 135 3- Fluorocyclobutanamine hydrochloride

125.57 0.015 — 0.120 136 2- Cyclopropylethanamine

 85.15 0.010 — 0.120 137 2- Ethoxycyclopropanamine

101.15 0.012 — 0.120 138 (2-Aminocyclopropyl) methanol

 87.12 0.010 — 0.120

A stock solution of1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (358 mg) was prepared in DMF (7.7 mL), along with HATU (502 mg),and DIPEA (0.57 mL), and was then capped and sonicated, before beingaliquoted (0.7 mL) into vials containing the listed amine monomers (0.12mmol). These were sealed and sonicated, then allowed to stand at rt for18 h. The samples were then directly injected and purified by MDAP (HighpH). The solvent was removed using a plate dryer to give the requiredproducts as indicated in the example table.

EXAMPLES

Ex Mass Yield Rt No. Name Structure (mg) (%) [MH]⁺ (min)* 1351-((1H-Indol-4- yl)methyl)-N5-(3- fluorocyclobutyl)- N3-methyl-2-oxo-1,2- dihydropyridine- 3,5-dicarboxamide

24 55 397 0.85 136 1-((1H-Indol-4- yl)methyl)-N5-(2- cyclopropylethyl)-N3-methyl-2-oxo- 1,2- dihydropyridine- 3,5-dicarboxamide

26 61 393 0.93 137 (+/−)-1-((1H- Indol-4- yl)methyl)-N5-(2-ethoxycyclopropyl)- N3-methyl-2-oxo- 1,2- dihydropyridine-3,5-dicarboxamide, single diastereomer with unknown relativestereochemistry

23 50 409 0.85 138 (+/−)-1-((1H- Indol-4- yl)methyl)-N5-(2-(hydroxymethyl) cyclopropyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

27 62 395 0.71 *All LCMS were conducted using 2 min formic.

Example 139:(+/−)-1-((1H-Indol-4-yl)methyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (150 mg, 0.304 mmol, 66% purity by wt), and HATU (174 mg, 0.456mmol) in DMF (1.217 mL) stirred at rt was added(trans)-2-methylcyclopropanamine (43.3 mg, 0.609 mmol, commerciallyavailable from, for example, Enamine) and DIPEA (106 μL, 0.609 mmol).The reaction was stirred at rt for 3 h. The reaction mixture was pouredonto water (30 mL) and extracted with ethyl acetate (4×30 mL). Thecombined organics were washed with brine, dried through a hydrophobicfrit and evaporated in vacuo to yield the crude product as a yellowsolid (223 mg). The solid was loaded in dichloromethane/methanol onto a10 g SNAP cartridge and purified via Biotage SP4, eluting from 0-50%(3:1 ethyl acetate:ethanol)/cyclohexane. The relevant fractions werecombined and evaporated in vacuo to yield the purified product (48 mg).

It was noted that the product had precipitated on silica and the columnwas flushed with 50% ethanol in ethyl acetate. The recovered fractionswere combined and evaporated in vacuo to yield further product as ayellow solid (91 mg). This sample was dissolved in MeOH:DMSO (1:1, 1 mL)and purified by MDAP (Formic). The solvent was combined with the initialbatch of product (48 mg) and evaporated in vacuo to give(+/−)-1-((1H-indol-4-yl)methyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(98 mg, 0.259 mmol, 85% yield).

LCMS (2 min Formic): Rt=0.86 min, [MH]⁺=379.2.

Example 140:(+/−)-N3-Methyl-1-(3-methylbenzyl)-N5-((cis)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-(3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200.5 mg, 0.668 mmol) and HATU (310 mg, 0.815 mmol) in DMF (3 mL)was added 2-methylcyclopropanamine (94.1 mg, 1.323 mmol, commerciallyavailable from, for example, Fluorochem) and DIPEA (0.233 mL, 1.335mmol). The mixture was stirred at rt for 1.5 h. Further HATU (129 mg,0.339 mmol) and DIPEA (0.117 mL, 0.668 mmol) were added and stirringcontinued at rt for 0.5 h. The reaction mixture was concentrated under astream of nitrogen before being made up to 3 mL with DMSO. This was thendirectly purified by MDAP (High pH). The appropriate fractionscorresponding to the cis-diastereoisomer were concentrated under astream of nitrogen before being dissolved in a mixture ofdichloromethane/methanol (4 mL, 1:1), concentrated under a stream ofnitrogen and dried in vacuo to give the product as a creamsolid—(±)-N3-methyl-1-(3-methylbenzyl)-N5-((cis)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(11.3 mg, 0.032 mmol, 4.79% yield)

LCMS (2 min Formic): Rt=0.96 min, [MH]⁺=354.2.

The appropriate fractions corresponding to the trans-diastereoisomerwere also combined and concentrated in vacuo before being dissolved in amixture of dichloromethane/methanol (10 mL, 1:1), concentrated under astream of nitrogen and dried in vacuo to give the product as a whitesolid,yield—(±)-N3-methyl-1-(3-methylbenzyl)-N5-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(172.6 mg, 0.488 mmol, 73.1% yield).

Example 141:(+/−)-N5-Cyclopropyl-1-(3-(1-hydroxyethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN5-cyclopropyl-1-(3-formylbenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(183 mg, 0.518 mmol) in THF (10 mL) under nitrogen at −78° C. was addeddrop-wise a solution of methylmagnesium bromide (3M in diethyl ether)(0.690 mL, 2.071 mmol). The reaction was stirred at −78° C. for 45 min.The reaction was quenched with methanol while still at −78° C. Thesolution was warmed to ambient temperature and concentrated in vacuo.The residue was suspended in ethyl acetate (50 mL) and washed with water(50 mL). Some insoluble solid remained in the aqueous layer. The aqueouslayer was back extracted with ethyl acetate (2×20 mL) and the combinedorganics were washed with brine (10 mL), dried through a hydrophobicfrit and evaporated in vacuo to yield the crude product as a yellowglass (202 mg). The solid was loaded in the minimum volume ofdichloromethane onto a SNAP cartridge (10 g) and purified via BiotageSP4 flash chromatography, eluting from 15-75% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo to yield a pale yellow gum (145 mg). The sample wasdissolved in MeOH:DMSO (2×1 mL, 1:1) and purified by MDAP (High pH). Therelevant fractions were combined and evaporated in vacuo to yield thedesiredproduct—N5-cyclopropyl-1-(3-(1-hydroxyethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(62 mg, 0.156 mmol, 30.1% yield) as a yellow solid. This product wascombined with a second batch of the product prepared in an analogousmanner, by sonicating together in diethyl ether and evaporating in vacuotoyield—N5-cyclopropyl-1-(3-(1-hydroxyethyl)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(86.4 mg, 0.222 mmol, 42.9% yield) as a pale yellow solid.

LCMS (2 min Formic): Rt=0.69 min, [MH]⁺=370.2.

Example 142:N5-((1R,2R)-2-(Hydroxymethyl)cyclopropyl-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-N5-((trans)-2-(Hydroxymethyl)cyclopropyl)-1-(3-methoxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(161 mg, 0.418 mmol, for example from example 132) was separated intoits two enantiomers:

Analytical Method:

The racemate (˜0.5 mg) was dissolved in 50% EtOH/Heptane (1 mL), 20 uLwas injected onto the column. (Column: 4.6 mm id×25 cm Chiralpak IA, LotNo. IA00CE-KL030). This was eluted with 50% EtOH (+0.2%isopropylamine)/Heptane, f=1.0 mL/min, detector wavelength 230 nm, 4.Ref 550,100.

Preparative Method:

The racemate (˜151 mg) was dissolved in DCM (2 mL) and EtOH (4 mL) withheating. Injection: 3 mL of the solution was injected onto the column(Column: 30 mm×25 cm Chiralpak IA (5 μm), Lot No. IA11157-01) This waseluted with 50% EtOH (+0.2% isopropylamine)/Heptane (+0.2%isopropylamine), flow rate=30 mL/min, detector wavelength=215 nm, 4. Ref550, 100. Total number of injections: 2. Fractions from 18-23 min werebulked and labelled peak 1. Fractions from 26.5-36 min were bulked andlabelled peak 2. The bulked fractions were vac'ed down using a rotaryevaporator and then transferred to a weighed flask for final analysis asdescribed by the analytical method above. The final material wasrecovered from DCM and heptane in order to obtain a solid.

Peak 1, Example 142, was collected as a white solid. (46 mg, 0.119 mmol,28.6% yield)

LCMS (2 min Formic): Rt=0.75 min, [MH]⁺=386.1.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.35 (br. q, J=4.2 Hz, 1H) 8.80 (d,J=2.7 Hz, 1H) 8.69 (d, J=2.7 Hz, 1H) 8.56 (br. d, J=4.4 Hz, 1H) 7.27 (t,J=7.8 Hz, 1H) 6.82-6.92 (m, 3H) 5.25 (s, 2H) 4.48 (t, J=5.5 Hz, 1H) 3.73(s, 3H) 3.31-3.43 (m, 2H) 2.82 (d, J=4.9 Hz, 3H) 2.69-2.75 (m, 1H) 1.22(dqd, J=9.1, 6.1, 6.1, 6.1, 3.4 Hz, 1H) 0.63-0.72 (m, 2H).

Example 143:N5-Cyclopropyl-1-(indolin-4-ylmethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

tert-Butyl4-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)indoline-1-carboxylate(43 mg, 0.092 mmol) and TFA (0.5 mL, 6.49 mmol) were stirred at rt inDCM for 30 min (2 mL). The reaction mixture was concentrated and loadedonto a SCX cartridge (5 g, pre-conditioned with MeOH) and eluted withMeOH (20 mL) followed by 2M NH₃ in MeOH (20 mL). The ammonia fractionscontaining product were combined and concentrated to giveN5-cyclopropyl-1-(indolin-4-ylmethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(30 mg, 0.074 mmol, 80% yield) as a yellow solid.

LCMS (2 min Formic): Rt=0.45 min, [MH]⁺=367.2.

¹H NMR (400 MHz, MeOH-d₄) δ ppm 8.81 (d, J=2.7 Hz, 1H) 8.43 (d, J=2.7Hz, 1H) 6.97 (t, J=7.8 Hz, 1H) 6.61 (d, J=7.8 Hz, 1H) 6.47 (d, J=7.6 Hz,1H) 5.22 (s, 2H) 3.49 (t, J=8.4 Hz, 2H) 2.98 (t, J=8.4 Hz, 2H) 2.94 (s,3H) 2.79 (tt, J=7.3, 3.8 Hz, 1H) 0.74-0.81 (m, 2H) 0.58-0.63 (m, 2H).

Example 144:N5-Cyclopropyl-N3-methyl-1-((1-methyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-((1H-indol-4-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(50 mg, 0.137 mmol, for example, Example 67) in DMF (900 μL) was addedpotassium carbonate (47.4 mg, 0.343 mmol) and iodomethane (17.16 μL,0.274 mmol). The reaction was stirred at 80° C. for 2 h. A furtherportion of iodomethane (8.58 μL, 0.137 mmol) was added and stirring wascontinued for 19 h. A further portion of potassium carbonate (114 mg,0.823 mmol) and iodomethane (42.9 μL, 0.686 mmol) were added. Thereaction was continued for a further 24 h and was then concentrated invacuo and filtered through cotton wool, however the filter becameblocked. The filter was cleaned with methanol and the washings werecombined and concentrated in vacuo. The residue was refiltered throughcotton wool into a 1 mL vial, and diluted up to 1 mL with DMSO. Thesolution was purified by MDAP (Formic). The relevant fractions weredried under a stream of nitrogen to give the required productN5-cyclopropyl-N3-methyl-1-((1-methyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(12.3 mg, 0.031 mmol, 22.50% yield).

LCMS (2 min Formic): Rt=0.89 min, [MH]⁺=379.3.

Example 145:N5-Cyclopropyl-N3-methyl-1-((2-methyl-1H-benzo[d]imidazol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

tert-Butyl7-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-2-methyl-1H-benzo[d]imidazole-1-carboxylate(10 mg, 0.021 mmol) was dissolved in HCl in IPA (0.634 μL, 0.021 mmol)and allowed to stir at rt over 3 days. The reaction mixture wasconcentrated under vacuum, dissolved in methanol and loaded onto apre-conditioned SCX column (1 g). Methanol (10 mL) was then passedthrough the column followed by 2M methanolic ammonia. The methanolicammonia fractions were combined and concentrated under vacuum to givethe title compound (3.7 mg, 9.75 μmol, 46.8% yield).

LCMS (2 min Formic): Rt=0.42 min, [MH]⁺=380.2.

Example 146:1-(3-Methoxybenzyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(187 mg, 0.548 mmol) in DMF (3 mL) was added potassium carbonate (151mg, 1.095 mmol) and 1-(bromomethyl)-3-methoxybenzene (165 mg, 0.821mmol). The mixture was stirred at rt for 2 h. The reaction was quenchedby the addition of water (30 mL) and EtOAc (30 mL) then added. Thelayers were separated and the aqueous layer further extracted with EtOAc(2×30 mL). The combined organics were then back-extracted with water(2×30 mL) and then brine (2×20 mL). The organic layer was dried (Na₂SO₄)and concentrated in vacuo to afford the crude product as a yellow oil.This was taken up in DCM and added to a SNAP (25 g) silica cartridge,this was purified by flash SP4 chromatography, eluting with 40→100%EtOAc/cyclohexane. The appropriate pure fractions were collected andconcentrated in vacuo to afford the desired product as a colourlessoil—1-(3-methoxybenzyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(115 mg, 0.311 mmol, 56.8% yield)

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=370.1.

Example 147:N5-Cyclopropyl-N3-methyl-1-((3-methyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN5-cyclopropyl-N3-methyl-1-((3-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(60 mg, 0.113 mmol) in methanol (376 μL) and THF (751 μL) stirred undernitrogen at rt was added solid cesium carbonate (147 mg, 0.451 mmol) inone charge. The reaction was heated to 70° C. for 2 h. The reactionmixture was concentrated in vacuo and taken up in ethyl acetate (30 mL)and water (10 mL). The aqueous layer was extracted with ethyl acetate(2×10 mL) and the combined organics were washed with brine (10 mL),dried through a hydrophobic frit and evaporated in vacuo to yield thecrude product (38 mg). The sample was dissolved in MeOH:DMSO (1 mL, 1:1)and purified by MDAP (High pH). The solvent was dried under a stream ofnitrogen to giveN5-cyclopropyl-N3-methyl-1-((3-methyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(21 mg, 0.055 mmol, 49.3% yield) as an off white solid.

LCMS (2 min Formic): Rt=0.83 min, [MH]⁺=379.2.

Example 148:1-((1H-Indazol-7-yl)methyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-((1H-indazol-7-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (17 mg, 0.052 mmol) in DMF (2 mL) was added HATU (30 mg, 0.079mmol) followed by (1S,2S)-2-methylcyclopropanamine, hydrochloride (8 mg,0.074 mmol) and DIPEA (0.036 mL, 0.209 mmol). The resulting reactionmixture was stirred at rt under N₂ (formed a yellow solution) for 2.5 h.The crude reaction mixture was partitioned between ethyl acetate and asat. solution of LiCl. The organic layer was separated and the aqueouslayer further extracted with ethyl acetate. LCMS showed some productstill in the aqueous layer so this was further extracted with DCM. Thecombined organic layers were dried (Na₂SO₄) and conc. to give ˜5629 mgof a crude white solid contaminated with inorganics. This was purifiedby chromatography on SiO₂ (Biotage SNAP 10 g cartridge, eluting with0-100% of ethyl acetate/cyclohexane) to give1-((1H-indazol-7-yl)methyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(17 mg, 0.040 mmol, 77% yield) as a white solid.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=380.0.

Example 149:(+/−)-N5-((trans)-2-Ethylcyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(3-(2-Hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (150 mg, 0.433 mmol) was taken up in DMF (5 mL) and HATU (181 mg,0.476 mmol), followed by DIPEA (0.076 mL, 0.433 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then(trans)-2-ethylcyclopropanamine, hydrochloride (57.9 mg, 0.476 mmol,commercially available from, for example, Enamine) was added and thereaction allowed to stir overnight. The reaction mixture wasconcentrated under vacuum and partitioned between ethyl acetate (20 mL)and citric acid solution (20 mL). The ethyl acetate layer was separatedand washed with sodium bicarbonate solution (20 mL) and then washed withwater (20 mL). The ethyl acetate layer was concentrated under vacuum andpurified by MDAP (High pH). The appropriate fractions were combined andconcentrated under vacuum to give the title compound (152 mg, 0.368mmol, 85% yield) as a white solid. The solid was then dissolved inmethanol and passed through a pre-prepared 2 g aminopropyl cartridge.The product containing fractions were combined to give the titlecompound (101 mg, 0.244 mmol, 56.4%) as a white solid.

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=414.2.

Example 150:1-(Benzofuran-4-ylmethyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (44mg, 0.187 mmol), 4-(bromomethyl)benzofuran (45 mg, 0.213 mmol),potassium carbonate (55 mg, 0.398 mmol) and DMF (1 mL) were stirred at90° C. for 3 h. The suspension was partitioned between EtOAc (20 mL) andwater (20 mL), extracted with EtOAc (20 mL), dried over a hydrophobicfrit and concentrated to give 300 mg as a yellow oil. This was purifiedby chromatography on SiO₂ (Biotage SNAP 25 g cartridge, eluting with0-100% EtOAc/cyclohexane). The appropriate fractions were concentratedto give 20 mg as a colourless oil. This was purified by MDAP (Formic,sample injected in 1 mL, 1:1 DMSO:MeOH). The appropriate fractions wereconcentrated to give1-(benzofuran-4-ylmethyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(13 mg, 0.032 mmol, 17.12% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.87 min, [MH]⁺=366.1.

Example 151:N5-((trans)-2-(Hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1-((S*)-1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide,1:1 Mixture of Diastereomers at the cPr Stereocentres

(S*)-5-(methylcarbamoyl)-6-oxo-1-(1-(m-tolyl)ethyl)-1,6-dihydropyridine-3-carboxylicacid (147 mg, 0.468 mmol), HATU (263 mg, 0.692 mmol), DIPEA (0.25 mL,1.431 mmol), (+/−)-((trans)-2-aminocyclopropyl)methanol (85 mg, 0.976mmol, commercially available from, for example, Enamine) and DMF (2 mL)were stirred at rt under N₂ for 1 h.

Further HATU (283 mg, 0.744 mmol), DIPEA (0.25 mL, 1.431 mmol) and(+/−)-((trans)-2-aminocyclopropyl)methanol (79 mg, 0.907 mmol) wereadded and the reaction stirred for 30 min. The solution wasconcentrated, partitioned between EtOAc (20 mL) and water (20 mL),extracted with EtOAc (2×20 mL), dried over a hydrophobic frit andconcentrated to give 590 mg of a yellow oil. This was purified bychromatography on SiO₂ (Biotage SNAP 50 g cartridge, eluting with 0-50%(25% EtOAc in EtOH)/cyclohexane). The appropriate fractions wereconcentrated to giveN5-((trans)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1-((S*))-1-(m-tolyl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide(204 mg, 0.468 mmol, 100% yield) as a mixture of diastereoisomers at thecPr stereocentres and as a colourless oil.

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=384.2.

Example 152:(+/−)-1-(1-(1H-Indol-4-yl)ethyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN5-cyclopropyl-N3-methyl-2-oxo-1-(1-(1-tosyl-1H-indol-4-yl)ethyl)-1,2-dihydropyridine-3,5-dicarboxamide(40 mg, 0.075 mmol) in methanol (0.5 mL) and THF (1 mL) stirred undernitrogen at rt, cesium carbonate (186 mg, 0.571 mmol) was added and thereaction mixture was stirred at 70° C. for 1 h. The solution waspartitioned between EtOAc (10 mL) and water (10 mL), extracted withEtOAc (2×20 mL), dried over a hydrophobic frit and concentrated to give50 mg as an off white solid. This was purified by chromatography on SiO₂(Biotage SNAP 25 g cartridge, eluting with 0-100% EtOAc/cyclohexane).The appropriate fractions were concentrated to give1-(1-(1H-indol-4-yl)ethyl)-N5-cyclopropyl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(27 mg, 0.064 mmol, 86% yield) a colourless oil.

LCMS (2 min Formic): Rt=0.85 min, [MH]⁺=379.2.

Example 153:1-(3-(2-Hydroxyethoxy)benzyl)-N3-methyl-N5-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(3-(2-Hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (80 mg, 0.231 mmol) was taken up in DMF (2.5 mL) and HATU (97 mg,0.254 mmol) followed by DIPEA (0.081 mL, 0.462 mmol) were added. Thereaction mixture was allowed to stir for 5 min, then(1S,2S)-2-methylcyclopropanamine, hydrochloride (27.3 mg, 0.254 mmol)was added and the reaction allowed to stir overnight. The reactionmixture was concentrated under vacuum and partitioned between ethylacetate (20 mL) and citric acid solution (20 mL). The ethyl acetatelayer was separated and washed with sodium bicarbonate solution (20 mL)and then washed with water (20 mL). The ethyl acetate layer wasconcentrated under vacuum and purified by MDAP (High pH). Theappropriate fractions were combined and concentrated under vacuum togive the title compound (8 mg, 0.020 mmol, 8.67% yield) as a whitesolid.

LCMS (2 min Formic): Rt=0.76 min, [MH]⁺=400.2.

¹H NMR (400 MHz, MeOH-d₄) δ ppm 8.81 (d, J=2.7 Hz, 1H) 8.52 (d, J=2.9Hz, 1H) 7.27 (t, J=7.9 Hz, 1H) 6.84-7.00 (m, 3H) 5.27 (s, 2H) 4.03 (app.t, J=4.6 Hz, 2H) 3.85 (app. t, J=4.8 Hz, 2H) 2.94 (s, 3H) 2.48 (dt,J=7.3, 3.6 Hz, 1H) 1.11 (d, J=6.1 Hz, 3H) 0.91-1.03 (m, 1H) 0.78 (ddd,J=9.2, 5.3, 4.2 Hz, 1H) 0.52-0.59 (m, 1H).

Example 154:1-((1H-Indol-4-yl)methyl)-N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideand Example 155:1-((1H-Indol-4-yl)methyl)-N5-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (150 mg, 0.304 mmol), and HATU (174 mg, 0.456 mmol) in DMF (1.217mL) stirred at rt was added (+/−)-((trans)-2-aminocyclopropyl)methanol(53.0 mg, 0.609 mmol, commercially available from, for example, Enamine)and DIPEA (106 μl, 0.609 mmol). The reaction was stirred at rt for 2 h.The reaction mixture was poured onto water (30 mL) and extracted withethyl acetate (4×30 mL). The combined organics were washed with brine,dried through a hydrophobic frit and evaporated in vacuo to yield thecrude product as a yellow oil (214 mg). The oil was loaded inDCM/methanol onto a 25 g SNAP cartridge and purified viaBiotage SP4flash chromatography, eluting from 5-25% (80:20 DCM:methanol)/DCM. Therelevant fractions were combined and evaporated in vacuo, sonicated withdiethyl ether and evaporated again to yield the pure product1-((1H-indol-4-yl)methyl)-N5-((trans)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(109 mg, 0.263 mmol, 86% yield) as a white solid which was submitted forchiral purification chromatography.

Analytical Method:

The racemate (˜0.5 mg) was dissolved in 50% EtOH/Heptane (1 mL). 20 uLwas injected on column. (Column: 4.6 mmid×25 cm Chiralpak AD-H, Lot No.ADH0CE-PC014). This was eluted with 50% EtOH/Heptane, f=1.0 mL/min,detector wavelength=215 nm, 4. Ref 550,100

Prep Method:

The racemate (˜107 mg) was dissolved in EtOH (1 mL). Injection: 1 mL ofthe solution was injected onto the column. (Column: 30 mm×25 cmChiralpak AD-H (5 μm), Lot No. ADH13231-01). This was eluted with 50%EtOH/Heptane, f=30 mL/min, detector wavelength=215 nm, 4. Ref 550,100.Fraction Collection: Fractions from 17-26 min were bulked and labelledpeak 1, fractions from 34-50 min were bulked and labelled peak 2. Thebulked fractions were vac'ed down using a rotary evaporator and thentransferred to a weighed flask for final analysis as described by theanalytical method above.

The first elutingenantiomer—1-((1H-indol-4-yl)methyl)-N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(48 mg, 0.116 mmol, 38.0% yield).

LCMS (2 min Formic): Rt=0.69 min, [MH]⁺=395.2.

The second eluting enantiomer1-((1H-indol-4-yl)methyl)-N5-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(49 mg, 0.118 mmol, 38.8% yield).

LCMS (2 min Formic): Rt=0.70 min, [MH]⁺=395.2.

Example 156:1-(3-Methoxybenzyl)-N3-methyl-N5-((1R,2R)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN3-methyl-N5-((1R,2R)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(60 mg, 0.190 mmol) in DMF (1 mL) was added potassium carbonate (52.6mg, 0.380 mmol) and 1-(bromomethyl)-3-methoxybenzene (57.4 mg, 0.285mmol). The mixture was stirred at rt for 2 h. The reaction was quenchedby the addition of water (20 mL) and EtOAc (20 mL) then added. Thelayers were separated and the aqueous layer further extracted with EtOAc(2×20 mL). The combined organics were then back-extracted with water (20mL) and then brine (2×20 mL). The organic layer was dried (Na₂SO₄) andconcentrated in vacuo to afford the crude product as a yellow oil. Thiswas taken up in DCM and added to a SNAP (10 g) silica cartridge, thiswas purified by flash SP4 chromatography, eluting with 40→100%EtOAc/cyclohexane. The appropriate fractions were collected andconcentrated in vacuo to afford the desired product as a colourless oil(58 mg). The sample was taken up in DCM/MeOH and concentrated in vacuoat 45° C. (×3). The resultant colourlessgum—1-(3-methoxybenzyl)-N3-methyl-N5-((1R,2R)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(46 mg, 0.125 mmol, 65.5% yield) was re-analysed.

LCMS (2 min Formic): Rt=0.91 min, [MH]⁺=370.1.

Examples 157-268

Examples 157-268 were prepared in an analogous manner to the previousexamples

Ex Rt No. Name Structure [MH]⁺ (min)* 157 N5-Cyclopropyl-1-(cyclopropyl(phenyl)methyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

366.1 (formic) 0.99 158 1-Benzyl-N5- (cyclobutylmethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

354.0 (formic) 1.01 159 N5-Cyclobutyl-N3-methyl-2-oxo-1-(pyridin-4-ylmethyl)- 1,2-dihydropyridine-3,5- dicarboxamide

341.0 (formic) 0.46 160 N5-Cyclobutyl-N3-methyl-2-oxo-1-(pyridin-2-ylmethyl)- 1,2-dihydropyridine-3,5- dicarboxamide

341.0 (formic) 0.71 161 N5-Cyclobutyl-N3-methyl-2-oxo-1-(pyridin-3-ylmethyl)- 1,2-dihydropyridine-3,5- dicarboxamide

341.0 (formic) 0.51 162 N5-Cyclobutyl-1-(2- fluorobenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

358.0 (formic) 0.96 163 N5-Cyclobutyl-N3-methyl-1-((1-methyl-1H-pyrazol-4- yl)methyl)-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

344.0 (formic) 0.69 164 N5-Cyclobutyl-1-(2,5-dimethylbenzyl)-N3-methyl-2- oxo-1,2-dihydropyridine-3,5- dicarboxamide

368.0 (formic) 1.09 165 1-Benzyl-N5-((cis)-3-hydroxycyclobutyl)-N3-methyl- 2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

356.0 (formic) 0.73 166 1-Benzyl-N5-(3,3- difluorocyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

376.0 (formic) 0.94 167 tert-Butyl (6-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6- dihydropyridine-3-carboxamido)spiro[3.3]heptan- 2-yl)carbamate

495.2 (formic) 1.09 168 1-Benzyl-N3-methyl-2-oxo-N5-(2-phenylcyclobutyl)-1,2- dihydropyridine-3,5- dicarboxamide

416.1 (formic) 1.07 169 (cis)-3-(1-Benzyl-5-(methylcarbamoyl)-6-oxo-1,6- dihydropyridine-3- carboxamido)cyclobutanecarboxylic acid

384.0 (formic) 0.78 170 N5-Cyclobutyl-1-(isoquinolin-5-ylmethyl)-N3-methyl-2-oxo- 1,2-dihydropyridine-3,5- dicarboxamide

391.0 (formic) 0.55 171 (S)-N5-Cyclobutyl-N3-methyl-2-oxo-1-(1-phenylethyl)-1,2- dihydropyridine-3,5- dicarboxamide

354.0 (formic) 0.98 172 1-Benzyl-N5-cyclobutyl-N3- ethyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

354.1 (formic) 0.99 173 1-Benzyl-N5-(1- isobutylcyclopropyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

382.0 (formic) 1.09 174 1-Benzyl-N5-(3-methoxy-2,2-dimethylcyclobutyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

398.1 (formic) 0.96 175 1-Benzyl-N5-(3- ethoxycyclobutyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

384.1 (formic) 0.90 176 1-Benzyl-N3-methyl-N5-(3-methylcyclobutyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

354.0 (formic) 1.00 177 1-Benzyl-N5-(3-ethoxy-2- methoxycyclobutyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

414.1 (formic) 0.90 178 1-Benzyl-N3-methyl-2-oxo-N5-(1-propylcyclopropyl)-1,2- dihydropyridine-3,5- dicarboxamide

368.1 (formic) 1.02 179 (S)-N5-Cyclopropyl-N3- methyl-2-oxo-1-(1-phenylethyl)-1,2- dihydropyridine-3,5- dicarboxamide

340.0 (formic) 0.88 180 Methyl 4-((5- (cyclobutylcarbamoyl)-3-(methylcarbamoyl)-2- oxopyridin-1(2H)- yl)methyl)benzoate

398.0 (formic) 0.90 181 1-Benzyl-N5-(2- ethoxycyclopropyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

370.2 (formic) 0.88 182 N5-Cyclobutyl-N3-methyl-2-oxo-1-(quinolin-5-ylmethyl)- 1,2-dihydropyridine-3,5- dicarboxamide

391.2 (formic) 0.62 183 1-Benzyl-N5-((1S,3R)-3- hydroxycyclopentyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

370.3 (formic) 0.77 184 1-(3-Cyanobenzyl)-N5-cyclopropyl-N3-methyl-2-oxo- 1,2-dihydropyridine-3,5- dicarboxamide

351.1 (formic) 0.76 185 (+/−)-1-Benzyl-N5-((trans)-2-hydroxycyclohexyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

384.3 (formic) 0.84 186 (+/−)-1-Benzyl-N5-((cis)-2-hydroxycyclohexyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

384.3 (formic) 0.86 187 N5-Cyclopropyl-N3-methyl-1- ((6-methylpyridin-2-yl)methyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

341.1 (formic) 0.55 188 (R*)-1-Benzyl-N5-(2,2- difluorocyclopropyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

362.1 (formic) 0.88 189 (+/−)-1-Benzyl-N5-(2- hydroxycyclopentyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide, singlediastereomer, unknown relative stereochemistry

370.3 (formic) 0.80 190 N5-Cyclopropyl-N3-methyl-2-oxo-1-(3-phenylpropyl)-1,2- dihydropyridine-3,5- dicarboxamide

354.1 (formic) 0.93 191 N5-Cyclopropyl-N3-methyl-2- oxo-1-phenethyl-1,2-dihydropyridine-3,5- dicarboxamide

340.1 (formic) 0.87  59b N5-Cyclopropyl-N3-methyl-1-(3-(morpholinomethyl)benzyl)- 2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

425.3 (formic) 0.42 192 (+/−)-1-(2-fluorobenzyl)-N3- methyl-N5-((cis)-2-methylcyclopropyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

358.2 (formic) 0.89 193 (+/−)-1-(2-Fluorobenzyl)-N5- ((trans)-2-methoxycyclopropyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

358.2 (formic) 0.89 194 1-Benzyl-N5-((2- hydroxycyclohexyl)methyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

398.3 (formic) 0.92 195 N5-Cyclopropyl-N3-methyl-2- oxo-1-((1,2,3,4-tetrahydroisoquinolin-7- yl)methyl)-1,2- dihydropyridine-3,5-dicarboxamide hydrochloride

381.2 (formic) 0.42 196 (+/−)-1-Benzyl-N5-(((1R,2S)-2-hydroxycyclopentyl)methyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

384.3 (formic) 0.83 197 (+/−)-1-Benzyl-N5-(((cis)-2-hydroxycyclopentyl)methyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

384.3 (formic) 0.87 198 (+/−)-1-Benzyl-N5-(((trans)-2-hydroxycyclopentyl)methyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

384.3 (formic) 0.78 199 (+/−)-1-Benzyl-N5-(((cis)-3-hydroxycyclopentyl)methyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

384.3 (formic) 0.81 200 1-Benzyl-N5-(((trans)-4-hydroxycyclohexyl)methyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

398.4 (formic) 0.80 201 1-Benzyl-N5-(((cis)-4-hydroxycyclohexyl)methyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

398.4 (formic) 0.82 202 Methyl 4-((5- (cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2- oxopyridin-1(2H)- yl)methyl)benzoate

384.1 (formic) 0.81 203 N5-Cyclopropyl-1-(3- ((dimethylamino)methyl)benzyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

383.3 (High pH) 0.83 204 1-(2-Fluorobenzyl)-N5- ((1R*,2R*)-2-methoxycyclopropyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

374.1 (formic) 0.83 205 (R)-N5-(6- Aminospiro[3.3]heptan-2-yl)-N3-methyl-2-oxo-1-(1- phenylethyl)-1,2- dihydropyridine-3,5-dicarboxamide

409.0 (formic) 0.58 206 (+/−)-1-Benzyl-N5-(((1R,3S)- 3-hydroxycyclohexyl)methyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

398.2 (formic) 0.82 207 N5-Cyclopropyl-1-(4-methoxy-3-methylbenzyl)-N3-methyl-2- oxo-1,2-dihydropyridine-3,5- dicarboxamide

370.2 (formic) 0.92 208 (+/−)-N5-((cis)-2- ethoxycyclopropyl)-1-(3-fluorobenzyl)-N3-methyl-2- oxo-1,2-dihydropyridine-3,5- dicarboxamide

388.2 (formic) 0.88 209 1-Benzyl-N5-((1R,2R)-2-hydroxycyclobutyl)-N3-methyl- 2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

356.1 (formic) 0.76 210 N5-Cyclopropyl-1-(4- (hydroxymethyl)benzyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

356.2 (formic) 0.64 211 (S*)-N5-Cyclopropyl-N3- methyl-2-oxo-1-(1-(m-tolyl)ethyl)-1,2- dihydropyridine-3,5- dicarboxamide

354.2 (formic) 0.95 212 (S*)-N5-Cyclopropyl-N3- methyl-2-oxo-1-(1-(o-tolyl)ethyl)-1,2- dihydropyridine-3,5- dicarboxamide

354.2 (formic) 0.94 213 (R*)-N5-Cyclopropyl-N3- methyl-2-oxo-1-(1-(o-tolyl)ethyl)-1,2- dihydropyridine-3,5- dicarboxamide

354.2 (formic) 0.94 214 1-(2-Fluoro-3-methylbenzyl)- N5-(2-(hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

388.0 (formic) 1.03 215 (+/−)-1-(2-Fluoro-3- methylbenzyl)-N3-methyl-N5-((trans)-2-methylcyclopropyl)- 2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

371.9 (formic) 0.98 216 1-Benzyl-N5-((1S*,3S*)-3- hydroxycyclohexyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

384.3 (formic) 0.81 217 1-Benzyl-N5-((1R*,3R*)-3- hydroxycyclohexyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

384.3 (formic) 0.81 218 1-Benzyl-N5-((1S*,3R*)-3- hydroxycyclohexyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

384.3 (formic) 0.80 219 1-Benzyl-N5-((1R,3S)-3- hydroxycyclohexyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

384.3 (formic) 0.80 220 N5-Cyclopropyl-N3-methyl-2- oxo-1-((1,2,3,4-tetrahydroisoquinolin-8- yl)methyl)-1,2- dihydropyridine-3,5-dicarboxamide

381.3 (formic) 0.44 221 1-((1H-Indol-4-yl)methyl)-N5-(6-aminospiro[3.3]heptan-2- yl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

433.9 (formic) 0.54 222 (+/−)-N5-((cis)-2- ethoxycyclopropyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

384.3 (formic) 0.94 223 (+/−)-N5-((trans)-2-ethoxycyclopropyl)-N3-methyl- 1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

384.3 (formic) 0.96 224 1-Benzyl-N5-(2,2- dimethylcyclopropyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

354.2 (formic) 0.96 225 1-(2-Fluorobenzyl)-N5- ((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

374.2 (formic) 0.74 226 1-(2-Fluorobenzyl)-N5- ((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

374.2 (formic) 0.74 227 N5-Cyclopropyl-1-(3-fluoro-5-methoxybenzyl)-N3-methyl-2- oxo-1,2-dihydropyridine-3,5- dicarboxamide

374.2 (formic) 0.88 228 N5-Cyclopropyl-N3-methyl-2- oxo-1-((1,2,3,4-tetrahydroquinolin-5- yl)methyl)-1,2- dihydropyridine-3,5- dicarboxamide

381.2 (formic) 0.58 229 1-(2-Fluoro-5-methylbenzyl)- N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

388.2 (formic) 0.81 230 1-(2-Fluoro-5-methylbenzyl)- N5-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

388.2 (formic) 0.81 231 N5-((1S*,2S*)-2- (Hydroxymethyl)cyclopropyl)-1-(3-methoxybenzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

386.2 (formic) 0.75 232 N5-((1R*,2R*)-2- ethoxycyclopropyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

384.2 (formic) 0.96 233 N5-((1S*,2S*)-2- Ethoxycyclopropyl)-N3-methyl-1-(3-methylbenzyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

384.2 (formic) 0.96 234 1-(4-Fluoro-3-methylbenzyl)- N5-((1R*,2R)-2-(hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

388.2 (formic) 0.83 235 1-(4-Fluoro-3-methylbenzyl)- N5-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

388.2 (formic) 0.83 236 1-(3-Fluorobenzyl)-N5- ((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

374.1 (formic) 0.75 237 1-(3-Fluorobenzyl)-N5- ((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

374.1 (formic) 0.74 238 (+/−)-N5-((trans)-2- ethoxycyclopropyl)-1-(2-fluoro-3-methylbenzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

402.2 (formic) 0.97 239 N5-Cyclopropyl-1-(4-fluoro-3-methoxybenzyl)-N3-methyl-2- oxo-1,2-dihydropyridine-3,5- dicarboxamide

374.1 (formic) 0.85 240 1-((1H-Indol-3-yl)methyl)-N5-cyclopropyl-N3-methyl-2-oxo- 1,2-dihydropyridine-3,5- dicarboxamide

365.2 (formic) 0.83 241 1-(3-Fluorobenzyl)-N3-methyl- N5-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

358.1 (formic) 0.92 242 1-(3-Fluorobenzyl)-N3-methyl- N5-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

358.2 (formic) 0.92 243 (+/−)-1-Benzyl-N5-((trans)-2-methoxycyclobutyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

370.1 (formic) 0.76 244 N5-Cyclopropyl-1-(2- hydroxybenzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

342.2 (formic) 0.76 245 N5-Cyclopropyl-N3-methyl-1- ((1-methyl-1H-benzo[d]imidazol-4- yl)methyl)-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

380.3 (formic) 0.75 246 N5-Cyclopropyl-1-(3-fluoro-5-methylbenzyl)-N3-methyl-2- oxo-1,2-dihydropyridine-3,5- dicarboxamide

358.1 (formic) 0.92 247 (+/−)-N3-Methyl-N5-((trans)-2-methylcyclopropyl)-1-(3- (morpholinomethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

439.2 (formic) 0.48 248 (R*)-1-Benzyl-N5-(2,2- dimethylcyclopropyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

354.1 (formic) 0.96 249 (S*)-1-Benzyl-N5-(2,2- dimethylcyclopropyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

354.1 (formic) 0.96 250 (+/−)-N5-Cyclopropyl-N3-methyl-2-oxo-1-((4,5,6,7- tetrahydro-1H- benzo[d]imidazol-4-yl)methyl)-1,2- dihydropyridine-3,5- dicarboxamide

370.2 (formic) 0.46 251 N3-Methyl-1-(3- methylbenzyl)-N5-((1R*,2R*)-2-methylcyclopropyl)-2-oxo- 1,2-dihydropyridine-3,5- dicarboxamide

354.2 (formic) 0.98 252 N3-Methyl-1-(3- methylbenzyl)-N5-((1S*,2S*)-2-methylcyclopropyl)-2-oxo- 1,2-dihydropyridine-3,5- dicarboxamide

354.2 (formic) 0.98 253 N5-((1R*,2R*)-2- Ethoxycyclopropyl)-1-(2-fluoro-5-methylbenzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

402.2 (formic) 0.96 254 N5-((1S*,2S*)-2- Ethoxycyclopropyl)-1-(2-fluoro-5-methylbenzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

402.2 (formic) 0.96 255 N5-((1R*,2R*)-2- Ethoxycyclopropyl)-1-(2-fluoro-3-methylbenzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

402.2 (formic) 0.97 256 N5-((1S*,2S*)-2- Ethoxycyclopropyl)-1-(2-fluoro-3-methylbenzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

402.2 (formic) 0.97 257 1-(4-Fluoro-3-methylbenzyl)-N3-methyl-N5-((1R*,2R*)-2- methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

372.2 (formic) 1.00 258 1-(4-Fluoro-3-methylbenzyl)-N3-methyl-N5-((1S*,2S*)-2- methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

372.2 (formic) 1.00 259 N3-Methyl-N5-((1R*,2R*)-2-methylcyclopropyl)-2-oxo-1- ((R)-1-phenylethyl)-1,2-dihydropyridine-3,5- dicarboxamide

354.2 (formic) 0.97 260 N3-Methyl-N5-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1- ((R)-1-phenylethyl)-1,2-dihydropyridine-3,5- dicarboxamide

354.3 (formic) 0.96 261 N5-Cyclopropyl-1-(1-(3- methoxyphenyl)ethyl)-N3-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

370.2 (formic) 0.89 262 (+/−)-1-(3-(2- Hydroxyethoxy)benzyl)-N5-((trans)-2- (hydroxymethyl)cyclopropyl)- N3-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

416.2 (formic) 0.62 263 1-(Benzofuran-3-ylmethyl)-N5-cyclopropyl-N3-methyl-2- oxo-1,2-dihydropyridine-3,5- dicarboxamide

366.1 (formic) 0.91 264 (+/−)-N5-((trans)-2- ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

430.3 (formic) 0.74 265 (R*)-N5-Cyclopropyl-1-(3-(1-hydroxyethyl)benzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

370.2 (formic) 0.71 266 (S*)-N5-Cyclopropyl-1-(3-(1-hydroxyethyl)benzyl)-N3- methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

370.3 (formic) 0.71 267 N5-((trans)-2- (Hydroxymethyl)cyclopropyl)-N3-methyl-2-oxo-1-((S*)-1- (m-tolyl)ethyl)-1,2- dihydropyridine-3,5-dicarboxamide, 1:1 mix of trans-diastereomers at cPr stereocentres

384.2 (formic) 0.85 268 N5-Cyclopropyl-1-((2,3- dihydrobenzofuran-3-yl)methyl)-N3-methyl-2-oxo- 1,2-dihydropyridine-3,5- dicarboxamide

368.2 (formic) 0.85

Example 269:1-((1H-Indol-4yl)methyl-N³-methyl-N⁵-(1R*,2R*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideExample 270:1-((1H-Indol-4-yl)methyl)-N³-methyl-N⁵-((1S*,2S*)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (150 mg, 0.30 mmol), and HATU (174 mg, 0.46 mmol) in DMF (1.2 mL)stirred at rt, was added (+/−)-(trans)-2-methylcyclopropanamine (43.3mg, 0.61 mmol, commercially available from, for example, Enamine) andDIPEA (106 μL, 0.61 mmol). The reaction was stirred at rt for 3 h. Thereaction mixture was poured onto water (30 mL) and extracted with ethylacetate (4×30 mL). The combined organics were washed with brine, driedthrough a hydrophobic frit and evaporated in vacuo to yield the crudeproduct as a yellow solid (223 mg). The solid was loaded indichloromethane/methanol onto a 10 g SNAP cartridge and purified viaBiotage SP4 flash chromatography, eluting from 0-50% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo to yield the purified product (48 mg). It was notedthat the product had precipitated on silica and the column was flushedwith 50% ethanol in ethyl acetate. The recovered fractions were combinedand evaporated in vacuo to yield further impure product as a yellowsolid (91 mg). The sample was dissolved in 1:1 MeOH:DMSO (1 mL) andpurified by MDAP (Formic). The desired fractions was combined with theresidue of the previous batch of product and evaporated in vacuo to give(+/−)-1-((1H-indol-4-yl)methyl)-N³-methyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(98 mg, 0.26 mmol, 85% yield).

The racemate (98 mg) was dissolved in EtOH (˜8-10 mL) with heat.Injection: 0.7 mL manual injections were made via a Rheodyne valve ontothe column (15% iPrOH/heptane, flow rate=42.5 mL/min (pressure: 94 bar),detection: UV Diode Array at 280 nm (Band width 1 40 nm, reference 400nm, bandwidth 100 nm), Column Chiralpak AD-H (250×30 mm, 5 μm).Fractions from 18-20.5 min were bulked and labelled peak 1. Fractionsfrom 22-26 min were bulked and labelled peak 2. The bulked fractionswere concentrated in vacuo, then taken up in EtOH and transferred toweighed flasks which were blown down to dyness under a stream ofnitrogen gas.

The fractions corresponding to peak 1 were collected to afford Example269 (34 mg, 0.09 mmol, 30% yield) as a white solid.

LCMS (2 min formic): Rt=0.86 min, [MH]⁺=379.2.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.25 (br. s., 1H) 9.40-9.49 (m, 1H)8.77-8.82 (m, 1H) 8.56 (d, J=2.7 Hz, 1H) 8.52 (d, J=3.9 Hz, 1H)7.34-7.41 (m, 2H) 7.06 (t, J=7.7 Hz, 1H) 6.83 (d, J=7.1 Hz, 1H) 6.50 (t,J=2.0 Hz, 1H) 5.54 (s, 2H) 2.84 (d, J=4.6 Hz, 3H) 2.43-2.49 (m, 1H) 1.02(d, J=6.1 Hz, 3H) 0.84-0.93 (m, 1H) 0.70 (dt, J=8.9, 4.5 Hz, 1H)0.40-0.48 (m, 1H)

The fractions corresponding to peak 2 were collected to afford Example270 (37 mg, 0.10 mmol, 32% yield) as a white solid.

LCMS (2 min formic): Rt=0.86 min, [MH]⁺=379.2.

Example 271:1-((1H-Pyrrolo[3,2-c]pyridin-4-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a suspension ofN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (55mg, 0.23 mmol) in acetonitrile (2.3 mL) was added triphenylphosphine(184 mg, 0.70 mmol), triethylamine (0.068 mL, 0.49 mmol) and DIAD (0.136mL, 0.701 mmol). The reaction was stirred at rt under nitrogen for 5 h.Further portions of triphenylphosphine (184 mg, 0.70 mmol) and DIAD(0.136 mL, 0.70 mmol) were added. After 21 h, the reaction mixture waspoured onto saturated aqueous sodium bicarbonate (10 mL) and extractedwith ethyl acetate (3×15 mL). The combined organics were dried through ahydrophobic frit and evaporated in vacuo to yield the crude product (727mg). The residue was dry loaded in methanol onto a 50 g SNAP cartridgeand purified by Biotage SP4 flash chromatography, eluting from 18-88%(80:20 DCM:2M methanolic ammonia)/DCM. Poor separation was achieved andall fractions containing product were recombined and evaporated in vacuoto yield a clear glass (41 mg). The sample was dissolved in 1:1MeOH:DMSO (1 mL) and purified by MDAP (High pH). The solvent was driedunder a stream of nitrogen to give1-((1H-pyrrolo[3,2-c]pyridin-4-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(3.2 mg, 8.32 μmol, 4% yield) as a white solid.

LCMS (2 min High pH): Rt=0.66 min, [MH]⁺=366.4.

Example 272:N⁵-Cyclopropyl-N³-methyl-1-((2-methyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution ofN⁵-cyclopropyl-N³-methyl-1-((2-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(75 mg, 0.14 mmol) in methanol (469 μL) and THF (939 μL) stirred undernitrogen at rt was added solid cesium carbonate (144 mg, 0.44 mmol) inone charge. The reaction mixture was heated to 70° C. for 8 h on a timerthen cooled to rt. The mixture was left to stand for 10 h before heatingwas resumed for a further 6 h. A further portion of cesium carbonate (92mg, 0.28 mmol) was added and the mixture was heated for a further 18 h.The reaction mixture was then concentrated in vacuo and partitionedbetween water (50 mL) and ethyl acetate (20 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×10mL). The combined organics were washed with brine (10 mL), dried througha hydrophobic frit and evaporated in vacuo to yield the crude product asa yellow solid (45 mg). The sample was loaded in dichloromethane onto a10 g SNAP cartridge and purified via Biotage SP4 flash chromatography,eluting from 13-63% (3:1 ethyl acetate:ethanol)/cyclohexane. Therelevant fractions were combined and evaporated in vacuo to yield thedesired productN⁵-cyclopropyl-N³-methyl-1-((2-methyl-1H-indol-4-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(38 mg, 0.10 mmol, 68% yield) as a white solid.

LCMS (2 min High pH): Rt=0.84 min, [MH]⁺=379.2.

Example 273:1-(3-(Difluoromethoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(55 mg, 0.22 mmol), 1-(bromomethyl)-3-(difluoromethoxy)benzene (62.8 mg,0.27 mmol), potassium carbonate (69 mg, 0.50 mmol) and DMF (2 mL) werestirred at 90° C. After 1.5 h the suspension was partitioned betweenEtOAc (10 mL) and LiCl solution. (10 mL), extracted with EtOAc (2×10mL), washed with brine, dried over a hydrophobic frit and concentratedto give the crude product (150 mg) as a colourless oil. This waspurified by chromatography on SiO₂ (Biotage SNAP 25 g cartridge, elutingwith 10-65% (25% EtOH in EtOAc)/cyclohexane). The desired fractions wereconcentrated to give1-(3-(difluoromethoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2dihydropyridine-3,5-dicarboxamide (39 mg, 0.087 mmol, 39.2% yield) as acolourless oil. This was further purified by MDAP (Formic). Theappropriate fractions were concentrated to give1-(3-(difluoromethoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(39 mg, 0.09 mmol, 39% yield) as a white solid.

LCMS (2 min Formic): Rt=0.97 min, [MH]⁺=406.2.

Example 274:N⁵-Cyclopropyl-1-(3-(difluoromethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

N⁵-Cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (99mg, 0.42 mmol), 1-(bromomethyl)-3-(difluoromethoxy)benzene (120 mg, 0.51mmol), potassium carbonate (110 mg, 0.80 mmol) and DMF (4 mL) werestirred at 90° C. After 1 h the suspension was partitioned between EtOAc(10 mL) and LiCl solution. (10 mL), extracted with EtOAc (2×10 mL),washed with brine, dried over a hydrophobic frit and concentrated togive the crude product (200 mg) as a cream solid. This was purified bychromatography on SiO₂ (Biotage SNAP 25 g cartridge, eluting with 10-65%(25% EtOH in EtOAc)/cyclohexane). The desired fractions wereconcentrated to give 50 mg as a white solid. This was further purifiedby MDAP (Formic). The appropriate fractions were concentrated to giveN⁵-cyclopropyl-1-(3-(difluoromethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(37 mg, 0.09 mmol, 20% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.90 min, [MH]⁺=392.2.

Example 275:N⁵-cyclopropyl-N³-methyl-2-oxo-1-(quinolin-7-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide

To a stirred solution ofN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (40mg, 0.17 mmol) and potassium carbonate (94 mg, 0.68 mmol) in DMF (850μL) under nitrogen at rt, was added 7-(bromomethyl)quinoline (110 mg,0.25 mmol) as a solution in DMF (850 μL). The reaction was stirred at rtfor 18 h. The reaction mixture was then poured onto saturated aqueouslithium chloride (30 mL) and extracted with ethyl acetate (3×15 mL). Theorganics were concentrated to yield the crude product as an orange oil(64 mg). The sample was loaded in dichloromethane/methanol onto a 10 gSNAP cartridge and purified by Biotage SP4 flash chromatography, elutingfrom 10-50% 2M methanolic ammonia/DCM to yield a yellow solid (25 mg).The sample was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP(High pH). The relevant fractions were evaporated in vacuo to yield thedesired productN⁵-cyclopropyl-N³-methyl-2-oxo-1-(quinolin-7-ylmethyl)-1,2-dihydropyridine-3,5-dicarboxamide(14 mg, 0.04 mmol, 22% yield) as a white solid.

LCMS (2 min high pH): Rt=0.78 min, [MH]⁺=377.4.

Example 276:1-((S*)-1-(3-Methoxyphenyl)ethyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of(S*)-1-(1-(3-methoxyphenyl)ethyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (116 mg, 0.21 mmol), and HATU (155 mg, 0.41 mmol) in DMF (2.1 mL)stirred at rt was added DIPEA (74 μL, 0.424 mmol) and(1S,2S)-2-methylcyclopropanamine hydrochloride (27 mg, 0.25 mmol) andthe reaction stirred for 2 h. A further portion of(1S,2S)-2-methylcyclopropanamine hydrochloride (8 mg, 0.07 mmol) wasadded. After 21 h, the reaction mixture was poured onto saturatedaqueous LiCl and extracted with ethyl acetate (1×15 mL, then 2×10 mL).The combined organics were washed with brine (10 mL), dried through ahydrophobic frit and evaporated in vacuo to yield the crude product as ayellow oil (176 mg). The oil was loaded in dichloromethane onto a 10 gSNAP cartridge and purified via Biotage SP4 flash chromatography,eluting from 8-38% (3:1 ethyl acetate:ethanol)/cyclohexane. The relevantfractions were combined and evaporated in vacuo to yield a clear gum (86mg). The sample was dissolved in 1:1 MeOH:DMSO (1 mL) and purified byMDAP (Formic). The solvent was dried under a stream of nitrogen and theresidue sonicated with diethyl ether and evaporated in vacuo to give1-((S*)-1-(3-methoxyphenyl)ethyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(60 mg, 0.15 mmol, 71% yield) as a white solid.

LCMS (2 min formic): Rt=0.97 min, [MH]⁺=384.2.

Example 277:1-(3-(2-Hydroxyethoxy)benzyl)-N⁵-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydrouridine-3,5-dicarboxamideExample 2781-(3-(2-Hydroxyethoxy)benzyl)-N⁵-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-1-(3-(2-Hydroxyethoxy)benzyl)-N⁵-((trans)-2-(hydroxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(50 mg) was submitted for chiral separation. The racemate (50 mg) wasdissolved in EtOH (1 mL). Injection: 1 mL of the solution was injectedonto the column (80% EtOH (+0.2% isopropylamine)/heptane (+0.2%isopropylamine), flow rate=20 mL/min, detection wavelength=215 nm, 4.Ref 550, 100, Column 30 mm×25 cm Chiralpak AD-H (5 μm), lot no.ADH12143-01). Total number of injections=1. Fractions from 18-23 minwere bulked and labelled peak 1. Fractions from 36-55 min were bulkedand labelled peak 2. The bulked fractions were concentrated in vacuo andthen transferred to weighed flasks. Final compounds were recovered fromDCM and heptane in order to obtain a solid.

The fractions corresponding to peak 1 were collected to afford—example277—1-(3-(2-hydroxyethoxy)benzyl)-N⁵-((1R*,2R*)-2-(hydroxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(18 mg, 36%) as a yellow solid.

LCMS (2 min Formic): Rt=0.62 min, [MH]⁺=416

The fractions corresponding to peak 2 were collected to afford—example278—1-(3-(2-hydroxyethoxy)benzyl)-N⁵-((1S*,2S*)-2-(hydroxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(18 mg, 36%) as a yellow solid.

LCMS (2 min Formic): Rt=0.62 min, [MH]⁺=416

Example 279:N⁵-((1R*,2R*)-2-Ethylcyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideExample 280:N⁵-((1S*,2S*)-2-Ethylcyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-N⁵-(-2-Ethylcyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(102 mg) was submitted for chiral separation. The racemate (102 mg) wasdissolved in EtOH (˜10 mL) with heat. Injection: 0.5 mL manualinjections via a Rheodyne valve were injected onto the column (80%iPrOH/heptane, flow rate=40 mL/min, detection: UV Diode Array at 280 nm(Band width 1 40 nm, reference 400 nm bandwidth 100 nm), Column 30 mm×25cm Chiralpak AD-H (5 μm). Fractions from 16.5-18 min were bulked andlabelled peak 1. Fractions from 20.5-22.5 min were bulked and labelledpeak 2. The bulked fractions were concentrated in vacuo and then takenup in EtOH (3×4 mL) and transferred to weighed vials. The solvent wasremoved under a stream of nitrogen to afford the two products.

The fractions corresponding to peak 1 were collected to afford—example279—N⁵-((1R*,2R*)-2-ethylcyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(40 mg, 40%).

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=414

The fractions corresponding to peak 2 were collected to afford—example280—N⁵-((1S*,2S*)-2-ethylcyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(41 mg, 41%).

LCMS (2 min Formic): Rt=0.84 min, [MH]⁺=414

Example 281:N⁵-((1R*,2R*)-2-Ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideExample 282:N⁵-((1S*,2S*)-2-Ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-N⁵-((trans)-2-Ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(126 mg) was submitted for chiral separation. The racemate (126 mg) wasdissolved in EtOH (˜10 mL) with heat. Injection: 0.6 mL manualinjections via a Rheodyne valve were injected onto the column (80%iPrOH/heptane, flow rate=42.5 mL/min, detection: UV Diode Array at 280nm (Band width 1 40 nm, reference 400 nm bandwidth 100 nm), Column 30mm×25 cm Chiralpak AD-H (5 μm). Fractions from 23-26 min were bulked andlabelled peak 1. Fractions from 29-33 min were bulked and labelled peak2. The bulked fractions were concentrated in vacuo and then taken up inEtOH (3×4 mL) and transferred to weighed vials. The solvent was removedunder a stream of nitrogen to afford the two products.

The fractions corresponding to peak 1 were collected to afford—example281—N⁵-((1R*,2R*)-2-ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(44 mg, 29%)

LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=430

The fractions corresponding to peak 2 were collected to afford—example282—N⁵-((1S*,2S*)-2-ethoxycyclopropyl)-1-(3-(2-hydroxyethoxy)benzyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(47 mg, 32%)

LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=430

Example 283:N⁵-(2-((trans)-4-Aminocyclohexyl)ethyl)-1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamidehydrochloride

To a suspension of tert-butyl((trans)-4-(2-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)ethyl)cyclohexyl)carbamate(75.5 mg, 0.15 mmol) in 1,4-dioxane (1 mL) was added hydrogen chloride(4M in 1,4-dioxane, 1.5 mL, 6.00 mmol) and the reaction mixture stirredat rt for 3.5 h. The reaction mixture was concentrated under a stream ofnitrogen and dried in vacuo to give a white solid;N⁵-(2-((trans)-4-aminocyclohexyl)ethyl)-1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamidehydrochloride (64.6 mg, 0.15 mmol, 98% yield).

LCMS (2 min formic) Rt=0.57 min, m/z=411 for [MH]⁺

Example 284:N⁵-(2-((cis)-4-Aminocyclohexyl)ethyl)-1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamidehydrochloride

To a suspension of tert-butyl((cis)-4-(2-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)ethyl)cyclohexyl)carbamate(70 mg, 0.14 mmol) in 1,4-dioxane (1 mL) was added hydrogen chloride (4Min 1,4-dioxane, 1.5 mL, 6.00 mmol) and the reaction mixture stirred atrt for 3.5 h. The reaction mixture was concentrated under a stream ofnitrogen and dried in vacuo to giveN⁵-(2-((cis)-4-aminocyclohexyl)ethyl)-1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamidehydrochloride (66.4 mg, 0.15 mmol, 108% yield) (containing approx. 0.5eq. 1,4-dioxane).

LCMS (2 min formic) Rt=0.62 min, m/z=411 for [MH]⁺

Example 285:1-((1H-Pyrrolo[3,2-c]pyridin-4-yl)methyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A solution ofN³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1-((1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(36.5 mg, 0.07 mmol) and potassium hydroxide (8.9 mg, 0.16 mmol) inmethanol (1 mL) and water (0.25 mL) was stirred at 50° C. for 2 h undernitrogen. The volatiles were evaporated in vacuo and the residuesuspended in water (3 mL) and dichloromethane (3 mL) and the layersseparated. The aqueous layer was extracted with further dichloromethane(3×3 mL). The aqueous layer was diluted with further water (approx. 10mL) and re-extracted with ethyl acetate (3×5 mL). To the aqueous layerwas added brine (approx. 2 mL) and it was re-extracted with ethylacetate (2×5 mL) and dichloromethane (2×5 mL). All organic phases werecombined and filtered through a cartridge fitted with a hydrophobicfrit. The filtrate was evaporated in vacuo to give a white solid;1-((1H-pyrrolo[3,2-c]pyridin-4-yl)methyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(18.7 mg, 0.05 mmol, 72% yield).

LCMS (2 min high pH) Rt=0.74 min, m/z=380 for [MH]⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.63 (br. s., 1H) 9.32 (q, J=4.6 Hz,1H) 8.83 (d, J=2.7 Hz, 1H) 8.73 (d, J=2.7 Hz, 1H) 8.57 (d, J=4.2 Hz, 1H)8.00 (d, J=5.9 Hz, 1H) 7.45-7.53 (m, 1H) 7.31 (d, J=5.9 Hz, 1H) 6.67 (d,J=2.9 Hz, 1H) 5.65 (s, 2H) 2.77 (d, J=4.9 Hz, 3H) 2.49-2.57 (obs, 1H)1.05 (d, J=6.1 Hz, 3H) 0.87-0.98 (m, 1H) 0.74 (dt, J=8.6, 4.6 Hz, 1H)0.48 (dt, J=7.3, 5.5 Hz, 1H)

Example 286:(±)-1-Benzyl-N⁵-((trans)-2-(methoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2,4,6-Trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(189 mg, 0.41 mmol), (±)-(trans)-2-(methoxymethyl)cyclopropanaminehydrochloride (147 mg, 0.27 mmol), DMAP (8 mg, 0.07 mmol), triethylamine(0.11 mL, 0.79 mmol) and THF (2.5 mL) were stirred at 45° C. under N₂.After stirring for 1 h, 2,4,6-trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(187 mg, 0.40 mmol) was added and the reaction stirred for 2 h. Thesuspension was partitioned between EtOAc (10 mL) and sodium bicarbonatesolution. (10 mL), extracted with EtOAc (2×10 mL), dried over ahydrophobic frit and concentrated to give the crude product (560 mg) asa yellow solid. This was purified by chromatography on SiO₂ (BiotageSNAP 50 g, eluting with 0-100% (25% ethanol in ethylacetate)/cyclohexane). The desired fractions were concentrated to give awhite solid. This was purified by MDAP (TFA). The appropriate fractionswere concentrated to give(±)-1-benzyl-N⁵-((trans)-2-(methoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(54 mg, 0.13 mmol, 49% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=370.2.

Example 287:N⁵-Cyclopropyl-1-(3-(2-hydroxyethyl)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2-(3-(Bromomethyl)phenyl)ethanol (247 mg, 1.15 mmol) was added to asolution ofN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(270 mg, 1.15 mmol) and potassium carbonate (317 mg, 2.30 mmol) in THF(15 mL). The reaction mixture was left to stir at rt for 2 h. Thereaction mixture was heated to 50° C. and left to stir under N₂overnight. The reaction mixture was then concentrated in vacuo andseparated between DCM and water. The organic solution was concentratedin vacuo, loaded in DCM and purified by Biotage Isolera flashchromatography using a SNAP 25 g silica cartridge and eluting with agradient of 0-10% EtOH/EtOAc to give, after concentration invacuo—N⁵-cyclopropyl-1-(3-(2-hydroxyethyl)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(310 mg, 0.08 mmol, 23% yield) as a white solid.

LCMS (2 min Formic): Rt=0.69 min, [MH]⁺=370

Example 288: (+/−)-tert-Butyl2-((trans)-2-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclopropyl)acetate

A mixture of 2,4,6-trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(1033 mg, 2.219 mmol) and triethylamine (0.619 mL, 4.44 mmol) in THF (15mL) was treated with (+/−)-tert-butyl2-((trans)-2-aminocyclopropyl)acetate (380 mg, 2.22 mmol) and DMAP (27.1mg, 0.22 mmol) and the resulting mixture was stirred at 50° C. After 2 hthe mixture was cooled to rt and concentrated in vacuo. The residue waspartitioned between EtOAc and a saturated NaHCO₃ solution and the layerswere separated. The aqueous phase was extracted with EtOAc and thecombined organics were washed with brine, dried over MgSO₄ andconcentrated in vacuo. Purification of the residue by Biotage SP4 flashchromatography on a 25 g silica column, eluting with a 50% GLOBAlgradient (AcOEt in hexanes) and concentration of the appropriatefractions provided a still impure product. 53 mg was purified by MDAP(Formic) to give tert-butyl5-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)pentanoate(1 mg, 2.27 μmol, 0.1% yield). The remaining impure product (243 mg) wasdissolved in DMSO (3 mL) and purified by preparative HPLC using theconditions below:

Preparative HPLC Method:

Injection: 3 mL

Column: CSH C18 column: 150×30 mm, 5 μm

Mobile Phase: B: acetonitrile; A: 10 mM ammonium bicarbonate in water,adjusted to pH 10 with ammonia solution

Time (min)/% A: 0/80, 3/80, 3.5/69, 25/58, 32/58, 35/1, 41/1

Temp: rt, Flow Rate: 40 mL/min

UV/MS Detection

UV detection: a summed signal from wavelength of 210 nm to 350 nm.

MS: Waters QDA

Ionisation mode: Positive Electrospray

Scan Range: 120 to 800 AMU

Scan Time: 0.5 s

Inter scan Delay: 0.1 s

The fractions were combined and dried using a Biotage V10 evaporator toafford (+/−)-tert-butyl2-((trans)-2-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclopropyl)acetate(143 mg, 0.33 mmol, 15%) as a white solid.

LCMS (2 min formic): Rt=1.06 min, [MH]⁺=440.3.

Example 289:N⁵-Cyclopropyl-N³-methyl-1-(3-(2-morpholinoethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A mixture ofN⁵-cyclopropyl-N³-methyl-2-oxo-1-(3-(2-oxoethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide(100 mg, 0.27 mmol), morpholine (0.047 mL, 0.54 mmol) and triethylamine(0.152 mL, 1.09 mmol) in DCM (3 mL) was stirred at rt for 45 min. Sodiumtriacetoxyborohydride (231 mg, 1.09 mmol) was added and the reaction wasstirred at rt for 24 h. The reaction mixture was then left to stand for9 days. Sat. NaHCO₃ (aq, 40 mL) was added and the mixture stirred at rtfor 15 min. The organic phase was separated. The aqueous phase wasextracted with DCM. The combined organics were passed through ahydrophobic frit and concentrated in vacuo. The resulting compound wasthen purified by MDAP (High pH). The appropriate fractions were combinedand evaporated to giveN⁵-cyclopropyl-N³-methyl-1-(3-(2-morpholinoethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(30 mg, 0.07 mmol, 25% yield)

LCMS (2 min Formic): Rt=0.44 min, [MH]⁺=439

Example 290:3-((5-(Cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoicacid

A solution of methyl3-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoate(62 mg, 0.16 mmol) and lithium hydroxide (9.4 mg, 0.39 mmol) intetrahydrofuran (1.5 mL) and water (0.25 mL) was stirred at rt undernitrogen for 75 h. Further tetrahydrofuran (1.5 mL) and water (0.5 mL)were added (because the solvent had evaporated) and stirring wascontinued for 2 h. It was then left to stand for 16 h before beingstirred for a further 5 h. The reaction mixture was diluted withwater/acetonitrile (5:1) to a total volume of 2 mL and was purified byMDAP (2×1 mL injection, formic). The required fractions from bothinjections were evaporated under a stream of nitrogen, the residues weresuspended in acetonitrile (ca. 2×5 mL), combined, evaporated under astream of nitrogen and dried in vacuo to give a white solid;3-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)benzoicacid (40.8 mg, 0.11 mmol, 68% yield)

LCMS (2 min formic) Rt=0.69 min, m/z=370 for [MH]⁺

Example 291:1-((1H-Pyrrolo[2,3-b]pyridin-3-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamidehydrochloride

To a suspension of tert-butyl3-((5-(cyclopropylcarbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(44 mg, 0.10 mmol) in 1,4-dioxane (0.75 mL) was added hydrogen chloride(4M in 1,4-dioxane, 0.75 mL, 3.00 mmol) and the reaction mixture stirredat rt for 16.75 h. The reaction mixture was transferred to a tarred vialusing a 1:1 mixture of dichloromethane/methanol (4 mL), concentratedunder a stream of nitrogen and dried in vacuo to give a beige solid;1-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide,hydrochloride (38.5 mg, 0.10 mmol, 101% yield).

LCMS (2 min formic) Rt=0.57 min, m/z=366 for [MH]⁺

Example 292:N⁵-Cyclopropyl-1-(3-(2-(dimethylamino)ethyl)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A mixture ofN⁵-cyclopropyl-N³-methyl-2-oxo-1-(3-(2-oxoethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide(81 mg, 0.22 mmol), dimethylamine hydrochloride (19.78 mg, 0.24 mmol)and triethylamine (0.154 mL, 1.10 mmol) in DCM (3 mL) was stirred at rtfor 45 min. Sodium triacetoxyborohydride (187 mg, 0.882 mmol) was addedand the reaction was stirred at rt overnight. Sat. NaHCO₃ (aq, 40 mL)was added and the mixture was stirred at rt for 15 min. The organicphase was separated. The aqueous phase was extracted with DCM. Thecombined organics were passed through a hydrophobic frit andconcentrated in vacuo. The resulting compound was then purified by MDAP(High pH). The appropriate fractions were combined and evaporated togive the crude product. This crude product was purified by BiotageIsolera flash chromatography using a SNAP 10 g silica cartridge andeluting with a gradient of 0-40% EtOAc/cyclohexane to give afterconcentration invacuo—N⁵-cyclopropyl-1-(3-(2-(dimethylamino)ethyl)benzyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(10 mg, 0.03 mmol, 11% yield) as a white solid.

LCMS (2 min Formic): Rt=0.45 min, [MH]⁺=397

Example 293:1-(Indolin-4-ylmethyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(300 mg, 1.204 mmol), indolin-4-ylmethanol (269 mg, 1.81 mmol) and2-(tributylphosphoranylidene)acetonitrile (0.995 mL, 3.79 mmol) werecombined in toluene (12.0 mL) and the reaction mixture heated in a 5 mLmicrowave vial at 120° C. for 30 min. The reaction mixture wasevaporated in vacuo, loaded in methanol and purified by SPE using asulphonic acid (SCX) 10 g cartridge and eluting with sequentialsolvents: methanol, 2M ammonia/methanol. The appropriate fractions werecombined and evaporated in vacuo to yield the crude product (711 mg) asan orange/brown gum. The residue was loaded in dichloromethane/methanolonto a 50 g SNAP cartridge and purified via Biotage SP4 flashchromatography, eluting from 15-75% (3:1 ethylacetate:ethanol)/cyclohexane. The relevant fractions were combined andevaporated in vacuo to yield1-(indolin-4-ylmethyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(284 mg, 0.64 mmol, 53% yield) as a yellow solid.

LCMS (2 min High pH): Rt=0.85 min, [MH]⁺=381.3.

Example 294:1-Benzyl-N⁵-((1S,2S)-2-(methoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Triethylamine (0.228 mL, 1.64 mmol) was added to a suspension of2,4,6-trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(381 mg, 0.82 mmol), (1S,2S)-2-(methoxymethyl)cyclopropanamine, HCl salt(106 mg, 0.55 mmol), and DMAP (16.66 mg, 0.14 mmol) in THF (8 mL). Thereaction mixture was heated to 45° C. under nitrogen overnight. Thereaction mixture was partitioned between ethyl acetate and sat. sodiumbicarbonate solution and the aqueous layer extracted with ethyl acetate(2×20 mL). The organic layer was passed through a hydrophobic frit andthe solvent removed in vacuo. The resulting oil was dissolved in DCM andpurified by flash chromatography using a 25 g Biotage SNAP column and agradient of 0-100% ethyl acetate/cyclohexane followed by 0-20%methanol/ethyl acetate. The product-containing fractions were combinedand the solvent removed in vacuo. The product was left to dry in vacuoovernight to give1-benzyl-N⁵-((1S,2S)-2-(methoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(90 mg, 0.24 mmol, 45% yield) as a pale orange solid.

LCMS (2 min formic): Rt=0.82 min, [MH]⁺=370.5.

Example 295:(+/−)-N⁵-((trans)-2-Ethylcyclopropyl)-1-(indolin-4-ylmethyl)-N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-tert-Butyl4-((5-(((trans)-2-ethylcyclopropyl)carbamoyl)-3-(methylcarbamoyl)-2-oxopyridin-1(2H)-yl)methyl)indoline-1-carboxylate(54 mg, 0.11 mmol) was dissolved in HCl (5-6M in IPA, 2 mL, 11.00 mmol)and allowed to stir at rt for 3 days. The reaction mixture wasconcentrated in vacuo, dissolved in MeOH and loaded in a pre-conditionedSCX column (1 g). MeOH was then passed through the column followed bymethanolic ammonia. The methanolic ammonia fractions were combined andconcentrated in vacuo to give the crude product. The resulting solid waspurified by MDAP (High pH) to give, after removal of thesolvent—(+/−)-N⁵-((trans)-2-ethylcyclopropyl)-1-(indolin-4-ylmethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(7 mg, 0.02 mmol, 16% yield) as a yellow solid.

LCMS (2 min Formic): Rt=0.61 min, [MH]⁺=395

Example 296:1-(3-(2-Hydroxyethyl)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2-(3-(Bromomethyl)phenyl)ethanol (173 mg, 0.80 mmol) was added to asuspension ofN³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(200 mg, 0.80 mmol) and potassium carbonate (222 mg, 1.61 mmol) in DMF(6 mL). The reaction mixture was left to stir at rt for 5 h. Thereaction mixture was concentrated in vacuo and separated between EtOAcand water. The organic solution was concentrated in vacuo, loaded in DCMand purified by Biotage Isolera flash chromatography using a SNAP 25 gsilica chromatography eluting with a gradient of 30-100%EtOAc/cyclohexane. The appropriate fractions were combined andconcentrated in vacuo to give1-(3-(2-hydroxyethyl)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(165 mg, 0.43 mmol, 54% yield) as a white solid.

LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=384

Example 297:1-Benzyl-N⁵-((1S,2R)-2-((dimethylamino)methyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(1R,2S)-2-((Dimethylamino)methyl) cyclopropanamine, hydrochloride (95mg, 0.22 mmol, 35% w/w) was added to a solution of 2,4,6-trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(113 mg, 0.24 mmol), triethylamine (0.092 mL, 0.66 mmol), and DMAP (6.74mg, 0.06 mmol) in THF (5 mL). The reaction mixture was heated to 45° C.under nitrogen overnight. The reaction mixture was partitioned betweenethyl acetate and sat. sodium bicarbonate solution. and extracted withethyl acetate (2×20 mL). The organic layer was passed through ahydrophobic frit and the solvent removed in vacuo. The resulting oil wasdissolved in DCM and purified by flash chromatography using a 50 gBiotage SNAP silica column and eluting with a gradient of 0-100% (25%ethanol in ethyl acetate)/cyclohexane to remove the major startingmaterial impurity, followed by a gradient of 0-100% (20% methanolicammonia in DCM)/cyclohexane. The product-containing fraction wasconcentrated and the oil dissolved in 1:1 DMSO:methanol and purified byMDAP (Formic). The product-containing fractions were concentrated andthe product left to dry under a stream of nitrogen overnight to give1-benzyl-N⁵-((1S,2R)-2-((dimethylamino)methyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(2.2 mg, 5.75 μmol, 3% yield) as a yellow solid.

LCMS (2 min formic): Rt=0.52 min, [MH]⁺=383.5.

Example 298:N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-((6-methylpyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A mixture ofN³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(42.8 mg, 0.17 mmol), (6-methylpyridin-2-yl)methanol (26.9 mg, 0.22 mmolcommercially available from, for example, Sigma-Aldrich) and2-(tributylphosphoranylidene)acetonitrile (0.090 mL, 0.34 mmol;commercially available from, for example, TCI) in toluene (1 mL) in asealed vial was heated at 100° C. for 0.5 h in a microwave reactor. Thevolatiles were evaporated from the mixture under a stream of nitrogenand the residue was redissolved in 3:1 methanol/DMSO (2 mL) and waspurified by MDAP (2×1 mL injection, formic). The required fractions fromboth injections were combined, evaporated and dried in vacuo to give adark brown oily residue. The residue was redissolved in 3:1methanol/DMSO (1 mL) and was further purified by MDAP (1×1 mL injection,formic). The required fractions were combined, evaporated and dried invacuo to give a pale yellow glass;N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-((6-methylpyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(42.2 mg, 0.12 mmol, 69% yield).

LCMS (2 min formic) Rt=0.63 min, m/z=355 for [MH]⁺

Example 299:(+/−)-1-Benzyl-N⁵-((trans)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-2-((trans)-2-(1-Benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclopropyl)aceticacid (100 mg, 0.26 mmol) was suspended in THF (5 mL) and Et₃N (0.073 mL,0.52 mmol) was added, then the mixture was stirred for 10 min andisobutyl chloroformate (0.041 mL, 0.31 mmol) was added. The mixture wasstirred for 1 h, then cooled in an ice bath and NaBH₄ (19.74 mg, 0.52mmol) was added in one portion. The mixture was stirred for 1 h. FurtherNaBH₄ (20 mg) was added and the mixture was stirred for another 1 h at0° C. The mixture was quenched by the addition of sat. NH₄Cl (aq, 10mL), then extracted with EtOAc. The organic layer was dried and thecrude product was dissolved in DCM and loaded onto a 10 g silica column,and purified by flash chromatography eluting with 0-25% EtOH/EtOAc. Theproduct-containing fractions were evaporated in vacuo to give(+/−)-1-benzyl-N⁵-(-2-((trans)-2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(2.2 mg, 5.96 μmol, 2% yield)

LCMS (2 min High pH): Rt=0.83 min, [MH]⁺=370

Example 300:N⁵-Cyclopropyl-1-((1-(2-hydroxyethyl)-1H-indol-3-yl)methyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of1-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)methyl)-N⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(34 mg, 0.07 mmol) in tetrahydrofuran (1 mL) was added TBAF (1M in THF,0.13 mL, 0.13 mmol) and the reaction mixture stirred at rt for 1.5 h.

The solvent was evaporated under a stream of nitrogen to give agreen/brown oil which was dissolved in dichloromethane (2 mL), loadedonto a 10 g SNAP silica cartridge and purified by flash chromatographyeluting with a gradient of 0-10% ethanol in ethyl acetate. The requiredfractions were combined and concentrated in vacuo, before beingdissolved in a 1:1 mixture of dichloromethane/methanol (10 mL),transferred to a tarred vial, concentrated under a stream of nitrogenand dried in vacuo to give a cream solid;N⁵-cyclopropyl-1-((1-(2-hydroxyethyl)-1H-indol-3-yl)methyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(12.1 mg, 0.03 mmol, 46% yield).

LCMS (2 min formic) Rt=0.79 min, m/z=409 for [MH]⁺

Example 301:N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-(3-(2-morpholinoethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A mixture ofN³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1-(3-(2-oxoethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide(150 mg, 0.39 mmol), morpholine (0.069 mL, 0.79 mmol) and triethylamine(0.219 mL, 1.57 mmol) in DCM (4 mL) was stirred at rt for 45 min. Sodiumtriacetoxyborohydride (333 mg, 1.57 mmol) was added and the reaction wasstirred at rt for 24 h. Sat. NaHCO₃ (aq, 40 mL) was added and themixture was stirred at rt for 1 h. The organic phase was separated. Theaqueous phase was extracted with DCM. The combined organics were passedthrough a hydrophobic frit and concentrated in vacuo. The resultingcompound was then purified by MDAP (High pH). The appropriate fractionswere combined and evaporated. The solid was dissolved in MeOH and passedthrough a pre-prepared aminopropyl column (1 g). The appropriatefractions were combined and concentrated in vacuo to giveN³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-(3-(2-morpholinoethyl)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(31 mg, 0.07 mmol, 17% yield) as a white solid.

LCMS (2 min Formic): Rt=0.51 min, [MH]⁺=453

Example 302:1-Benzyl-N⁵-((1R,2R)-2-(methoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2,4,6-Trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(135 mg, 0.29 mmol), (1R,2R)-2-(methoxymethyl)cyclopropanamine,hydrochloride (76 mg, 0.28 mmol), DMAP (3.54 mg, 0.03 mmol),triethylamine (0.121 mL, 0.87 mmol) and THF (3 mL) were stirred at rtunder N₂. After stirring overnight this was concentrated to give thecrude product (320 mg). This was purified by chromatography on SiO₂(Biotage SNAP 50 g, eluting with 0-50% (25% ethanol in ethylacetate)/ethyl acetate). The desired fractions were concentrated to give1-benzyl-N⁵-((1R,2R)-2-(methoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(39 mg, 0.10 mmol, 33% yield) as a colourless oil.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=370.5.

Example 303:1-Benzyl-N⁵-((1R,2R)-2-(ethoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Triethylamine (0.116 mL, 0.83 mmol) was added to a solution containing2,4,6-trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(214 mg, 0.46 mmol), (1S,2S)-2-(ethoxymethyl)cyclopropanamine, HCl salt(160 mg, 0.42 mmol), and DMAP (12.73 mg, 0.10 mmol) in THF (5 mL). Thereaction mixture was heated to 45° C. under nitrogen for 4 h. Thereaction mixture was then diluted with sat. sodium bicarbonate solution.and extracted with ethyl acetate (2×20 mL). The organic layer was passedthrough a hydrophobic frit and the solvent removed in vacuo. Theresulting oil was dissolved in DCM and purified by flash chromatographyusing a 25 g Biotage SNAP silica column and eluting with a gradient of0-100% ethyl acetate/cyclohexane. The product-containing fractions werecombined and the solvent removed in vacuo. The product was left to dryin vacuo overnight to give1-benzyl-N⁵-((1R,2R)-2-(ethoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(31.3 mg, 0.08 mmol, 20% yield) as a pale yellow solid.

LCMS (2 min formic): Rt=0.88 min, [MH]⁺=384.5.

Example 304:1-(3-Hydroxybenzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-(3-Methoxybenzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(520 mg, 1.41 mmol) in DCM (6 mL) was cooled to 0° C. under N₂ and BBr₃(2.82 mL, 2.82 mmol, 1M in DCM) was added dropwise and allowed to stirunder N₂ at rt for 6 h. The reaction was quenched with MeOH andconcentrated in vacuo. The reaction mixture was dissolved in MeOH,loaded onto silica and purified by Biotage Isolera flash chromatographyusing a SNAP 50 g silica cartridge and eluting with a gradient of20-100% EtOAc/cyclohexane to give the crude product which was furtherpurified by MDAP (High pH). The appropriate fractions were combined andconcentrated in vacuo to give1-(3-hydroxybenzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(75 mg, 0.21 mmol, 15% yield) as a white solid.

LCMS (2 min Formic): Rt=0.77 min, [MH]⁺=356

Example 305:1-Benzyl-N⁵-((1S,2S)-2-(ethoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

Triethylamine (0.020 mL, 0.146 mmol) was added to a solution of2,4,6-trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(37.4 mg, 0.08 mmol), (1R,2R)-2-(ethoxymethyl)cyclopropanamine,hydrochloride salt (21 mg, 0.07 mmol), and DMAP (2.2 mg, 0.02 mmol). Thereaction mixture was heated to 45° C. under nitrogen for 5 h. Thereaction mixture was then diluted with sat. sodium bicarbonate solution.(15 mL) and the organic layer extracted with ethyl acetate (2×15 mL).The organic layer was passed through a hydrophobic frit and the solventremoved in vacuo. The resulting oil was dissolved in DCM and purified byflash chromatography using a 10 g Biotage SNAP silica column and elutingwith a gradient of 0-100% ethyl acetate/cyclohexane. The product wasleft to dry in vacuo for 4 h to give1-benzyl-N⁵-((1S,2S)-2-(ethoxymethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(1.8 mg, 4.69 μmol, 6% yield) as a pale yellow solid.

LCMS (2 min formic): Rt=0.88 min, [MH]⁺=384.2.

Example 306:1-(3-(2-Methoxyethoxy)benzyl)-N³-meth-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A mixture of1-(3-hydroxybenzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(55.8 mg, 0.16 mmol), 2-methoxyethanol (0.025 mL, 0.31 mmol) and2-(tributylphosphoranylidene)acetonitrile (0.082 mL, 0.31 mmol;commercially available from, for example, TCI) in toluene (1.0 mL) in asealed vial was heated at 100° C. for 30 min in a microwave reactor. Thesolvent was evaporated from the reaction mixture under a stream ofnitrogen. The brown oily residue was re-dissolved in methanol (2 mL) andwas purified by MDAP (2×1 mL injection, formic). The desired fractionsfrom both injections were combined and evaporated in vacuo to give apale yellow sticky solid;1-(3-(2-methoxyethoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(62.2 mg, 0.15 mmol, 96% yield)

LCMS (2 min formic) Rt=0.89 min, m/z=414 for [MH]⁺

Example 307:1-(3-((S)-2-Hydroxypropoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of(S)-1-(3-(2-hydroxypropoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (102 mg, 0.28 mmol) in DMF (2 mL) was added HATU (161 mg, 0.43mmol) followed by (1S,2S)-2-methylcyclopropanamine, hydrochloride (61mg, 0.57 mmol) and DIPEA (0.247 mL, 1.415 mmol). The resulting reactionmixture was stirred at rt under N₂ (formed yellow solution) o/n. Thereaction mixture was purified directly by MDAP (Formic). The fractionscontaining the desired product were partitioned between sat. NaHCO₃solution and DCM. The organic layer was extracted (2×20 mL), dried(Na₂SO₄) and concentrated in vacuo to give1-(3-((S)-2-hydroxypropoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(71 mg, 0.16 mmol, 55% yield) as a white solid.

LCMS (2 min Formic): Rt=0.82 min, [MH]⁺=414.3.

Example 308:N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-(3-(2-morpholinoethoxy)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A mixture of1-(3-hydroxybenzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(45.6 mg, 0.13 mmol), 2-morpholinoethanol (31.0 μL, 0.26 mmol;commercially available from, for example, Acros) and2-(tributylphosphoranylidene)acetonitrile (67.3 μL, 0.26 mmol;commercially available from, for example, TCI) in toluene (1.0 mL) in asealed vial was heated at 100° C. for a total of 1 h in a microwavereactor. The mixture was evaporated under a stream of nitrogen to removethe solvent and the residue was re-dissolved in methanol (1 mL) andpurified by MDAP (1×1 mL injection, high pH). The required fraction hadthe solvent evaporated under a stream of nitrogen to give a cream solid;N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-(3-(2-morpholinoethoxy)benzyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(41.6 mg, 0.09 mmol, 69% yield)

LCMS (2 min formic) Rt=0.51 min, m/z=469 for [MH]⁺

Example 309:1-(3-((R)-2-Hydroxypropoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A mixture of1-(3-hydroxybenzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(43.6 mg, 0.12 mmol), (R)-2-methyloxirane (43.0 μL, 0.61 mmol;commercially available from, for example, Alfa Aesar), triethylamine(34.2 μL, 0.25 mmol) and DMF (1 mL) in a sealed vial was heated at 150°C. for 30 min in a microwave reactor. Further (R)-2-methyloxirane (43.0μL, 0.61 mmol) and triethylamine (34.2 μL, 0.25 mmol) were added, thevial was re-sealed and the mixture heated at 150° C. for a further 2 h.The mixture was concentrated under a stream of nitrogen to a volume ofapproximately 0.3 mL, was diluted to 1 mL with methanol and directlypurified by MDAP (1×1 mL injection, formic). The required fraction hadthe solvent evaporated under a stream of nitrogen to give a cream solid;1-(3-((R)-2-hydroxypropoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(29.4 mg, 0.07 mmol, 58.0% yield)

LCMS (2 min formic) Rt=0.82 min, m/z=414 for [MH]⁺

Example 310:(+/−)-1-((1H-Indol-4-yl)methyl)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A solution of(+/−)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(50 mg, 0.08 mmol), NaOH (6.44 mg, 0.16 mmol) in methanol (2 mL) wasstirred under nitrogen at 70° C. for 3 h. The reaction mixture was thencooled to rt, diluted with water (50 mL) and extracted with EtOAc (2×50mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated to afford the crude compound.This was purified by flash chromatography using a 100-200 mesh silicagel column and eluting with 0-5% MeOH in DCM. The pure fractions werecollected, concentrated and dried to obtain(+/−)-1-((1H-indol-4-yl)methyl)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(30 mg, 0.07 mmol, 85% yield) as a yellow solid.

Separately, a solution of(+/−)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,2-dihydropyridine-3,5-dicarboxamide(100 mg, 0.16 mmol), NaOH (12.88 mg, 0.32 mmol) in methanol (2 mL) wasstirred under nitrogen at 70° C. for 3 h. The reaction mixture was thencooled to rt, diluted with water (50 mL) and extracted with EtOAc (2×50mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated to obtain the crude compound.This was purified by flash chromatography using a 100-200 mesh silicagel column and eluting with 0-5% MeOH in DCM. The pure fractions werecollected, concentrated and dried to obtain(+/−)-1-((1H-indol-4-yl)methyl)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(70 mg, 0.15 mmol, 93% yield) as a yellow solid.

The two batches of product were combined and submitted for preparativeHPLC following the conditions outlined below:

HPLC Preparative Conditions:

Mobile Phase A: 10 mM Ammonium Bicarbonate (aq.)

Mobile Phase B: acetonitrile

Column: Kromosil packed C18 (250*25 mm)

Method T/% B=0/50, 11/50, 11.5/100, 18/100, 18.5/50, 22/50

Flow rate: 20 mL/min

Solubility: ACN+Water+THF

Temp: Ambient

After preparative purification, the compound fraction was lyophilized toafford(+/−)-1-((1H-indol-4-yl)methyl)-N³-ethyl-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(35 mg, 0.09 mmol, 41% yield) as an off white solid.

LCMS (4.5 min RND-FA-4.5-MIN): Rt=1.97 min, [MH]⁺=393.2.

LCMS Conditions: RND-FA-4.5-MIN

Column: Acquity BEH C18 (50 mm×2.1 mm, 1.7 μm)

Mobile Phase: B: 0.05% formic acid in ACN; A: 0.05% formic acid in water

Time (min)/% B: 0/3, 0.4/3, 3.2/98, 3.8/98, 4.2/3, 4.5/3

Column Temp: 35° C., Flow Rate: 0.6 mL/min

Example 311:1-Benzyl-N⁵-((1S*,2R*)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideExample 312:1-Benzyl-N⁵-((1R*,2S*)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

The racemate,(+/−)-1-benzyl-N5-((trans)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(31 mg) was dissolved in EtOH (2 mL) with heat. Injection: 2 mL wasinjected onto the column (30% EtOH/heptane, flow rate=30 mL/min),detection: UV wavelength, 215 nm, 4. Ref 550, 100), Column: 30 mm×25 cmChiralcel OJ-H (5 μm) Lot No. OJH10027-01. Fractions from 10.5-13 minwere bulked and labelled peak 1. Fractions from 17-21 min were bulkedand labelled peak 2. The bulked fractions were concentrated in vacuo,then transferred to weighed flasks.

The fractions corresponding to peak 1 were collected to afford Example311 (12 mg)

LCMS (2 min high pH): Rt=0.83 min, [MH]⁺=370.3.

The fractions corresponding to peak 2 were collected to afford Example312 (13 mg)

LCMS (2 min high pH): Rt=0.83 min, [MH]⁺=370.3.

Example 313:(+/−)-1-((1H-Indol-4-yl)methyl)-N⁵-((trans)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

1-((1H-Indol-4-yl)methyl)-N⁵-((1S,2R)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(203 mg, 0.39 mmol) was taken up in THF (10 mL) and TBAF (1M in THF,0.777 mL, 0.78 mmol) was added. The reaction was stirred at rt for 4 h.The reaction was quenched with water (10 mL) then partitioned betweenEtOAc and brine (25 mL each). The aqueous layer was re-extracted withEtOAc (25 mL) and the combined organics were dried with Na₂SO₄, filteredthrough a hydrophobic frit and concentrated in vacuo to yield an orangeoil. The crude product was applied to a 10 g ULTRA SNAP cartridge in theminimum of DCM and purified by flash chromatography eluting with 10-50%(3:1 EtOAc:EtOH) in DCM. The appropriate fractions were concentrated invacuo to give(+/−)-1-((1H-indol-4-yl)methyl)-N⁵-((trans)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(148 mg, 0.34 mmol, 89% yield) as a cream solid.

LCMS (2 min High pH): Rt=0.79 min, [MH]⁺=409.4

Example 314:(+/−)-N³-Ethyl-1-(indolin-4-ylmethyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of (+/−)-tert-butyl4-((3-(ethylcarbamoyl)-5-(((trans)-2-methylcyclopropyl)carbamoyl)-2-oxopyridin-1(2b)-yl)methyl)indoline-1-carboxylate(400 mg, 0.26 mmol) in DCM (10 mL) stirred under nitrogen at 0° C., wasadded TFA (1.396 mL, 18.12 mmol). The reaction mixture was stirred at rtfor 30 min. The reaction mixture was then concentrated to afford thecrude product. This was purified by flash chromatography using a 100-200mesh silica gel column and eluting with 0-10% MeOH in DCM. The purefractions were collected, concentrated and dried to afford the desiredproduct which was still impure. The product was further purified bypreparative HPLC following the conditions below:

Preparative HPLC Conditions:

Mobile Phase A: 10 mM ammonium acetate (aq., pH 9)

Mobile Phase B: acetonitrile

Column: Xselect CSH C18 (150*19 mm), 5 μm

Method T/% B=0/35, 9.5/35, 10/100, 13/100, 13.5/35, 16/35

Flow rate: 18 mL/min

Solubility: ACN+Water+THF

Temp: Ambient

After preparative purification, the compound was lyophilized and dilutedwith DCM (100 mL), washed with water and the organic phase was thenwashed with saturated brine (25 mL), dried over sodium sulphate,filtered and evaporated in vacuo to afford the desired product. Thecompound was triturated with n-pentane and filtered, the filtrate wasconcentrated to give(+/−)-N³-ethyl-1-(indolin-4-ylmethyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(30 mg, 0.07 mmol, 28% yield) as an off white solid.

LCMS (4.5 min RND-FA-4.5-MIN): Rt=1.43 min, [MH]⁺=395.2.

LCMS Conditions: RND-FA-4.5-MIN

Column: Acquity BEH C18 (50 mm×2.1 mm, 1.7 μm)

Mobile Phase: B: 0.05% formic acid in ACN; A: 0.05% formic acid in water

Time (min)/% B: 0/3, 0.4/3, 3.2/98, 3.8/98, 4.2/3, 4.5/3

Column Temp: 35° C., Flow Rate: 0.6 mL/min

Example 315:(+/−)-N³-Ethyl-1-(3-(2-hydroxyethoxy)benzyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

A solution of(+/−)-N³-ethyl-1-(3-hydroxybenzyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(150 mg, 0.40 mmol), 1,3-dioxolan-2-one (139 mg, 1.58 mmol) and K₂CO₃(164 mg, 1.19 mmol) in DMF (2 mL) was stirred under nitrogen at 90° C.for 6 h. The reaction mixture was then quenched with water and extractedwith DCM (2×25 mL). The organic phase was washed with saturated brine(25 mL), dried over sodium sulphate, filtered and evaporated in vacuo toafford the crude product. This was purified by flash chromatographyusing a 100-200 mesh silica gel column and eluting with 0-10% MeOH inDCM. The pure fractions were collected, concentrated and dried to give(+/−)-N³-ethyl-1-(3-(2-hydroxyethoxy)benzyl)-N⁵-((trans)-2-methylcyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(45 mg, 0.10 mmol, 26% yield) as a white solid.

LCMS (4.5 min RND-FA-4.5-MIN): Rt=1.74 min, [MH]⁺=414.2.

LCMS Conditions: RND-FA-4.5-MIN

Column: Acquity BEH C18 (50 mm×2.1 mm, 1.7 μm)

Mobile Phase: B: 0.05% formic acid in ACN; A: 0.05% formic acid in water

Time (min)/% B: 0/3, 0.4/3, 3.2/98, 3.8/98, 4.2/3, 4.5/3

Column Temp: 35° C., Flow Rate: 0.6 mL/min

Example 316:(+/−)-1-((1H-Indol-4-yl)methyl)-N⁵-((trans)-2-(2-((2-aminoethyl)(methyl)amino)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-tert-Butyl(2-((2-((trans)-2-(1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)cyclopropyl)ethyl)(methyl)amino)ethyl)carbamate(44 mg, 0.08 mmol) was taken up in DCM (5 mL) and TFA (0.5 mL, 6.49mmol) added. The reaction was stirred at rt. After 90 min the reactionwas concentrated in vacuo. The crude product was purified by MDAP (highpH). The appropriate fractions were concentrated in vacuo to give(+/−)-1-((1H-indol-4-yl)methyl)-N⁵-((trans)-2-(2-((2-aminoethyl)(methyl)amino)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(3.9 mg, 7.98 μmol, 10% yield) as a cream solid.

LCMS (2 min High pH): Rt=0.81 min, [MH]⁺=465.4.

Example 317:1-((1H-Indol-4-yl)methyl)-N⁵-(trans-3-hydroxycyclobutyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a mixture of1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (56.0 mg, 0.17 mmol) and HATU (101.1 mg, 0.27 mmol) was added asolution of trans-3-aminocyclobutanoyl, hydrochloride (30.7 mg, 0.25mmol, commercially available from, for example, Activate Scientific) inDMF (1.5 mL). N,N-Diisopropylethylamine (0.105 mL, 0.602 mmol) was addedand the mixture was stirred at rt for 1 h. The reaction mixture wasconcentrated under a stream of nitrogen, diluted with acetonitrile to atotal volume of 2 mL and directly purified by MDAP (2×1 mL injection,formic). The required fractions from both injections were combined andevaporated in vacuo. The residue was suspended in dichloromethane andmethanol (1:1, ˜6 mL), transferred to a tared vial and the solventevaporated under a stream of nitrogen to give a cream solid;1-((1H-indol-4-yl)methyl)-N⁵-(trans-3-hydroxycyclobutyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(60.7 mg, 0.15 mmol, 89% yield)

LCMS (2 min formic) Rt=0.70 min, m/z=395 for [MH]⁺

Example 318:N⁵-Cyclopropyl-N³-methyl-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide

To a mixture ofN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(51.0 mg, 0.217 mmol) in toluene (1 mL) was added(3-(trifluoromethyl)phenyl)methanol (0.038 mL, 0.28 mmol, commerciallyavailable from, for example, Alfa Aesar) and2-(tributylphosphoranylidene)acetonitrile (0.114 mL, 0.43 mmol;commercially available from, for example, TCI) in a microwave vial. Thevial was sealed and the mixture heated in a microwave reactor at 100° C.for 30 min. The volatiles were evaporated under a stream of nitrogen togive a dark brown viscous oil which was redissolved in DMSO (2 mL) anddirectly purified by MDAP (2×1 mL injection, high pH). The requiredfractions from both injections were evaporated under a stream ofnitrogen, redissolved in methanol (approx. 0.5 mL each) anddichloromethane (approx. 2 mL each) and combined. This solution wasevaporated under a stream of nitrogen and the residue dried in vacuo togive a light yellow oily solid which was redissolved in DMSO (2 mL) andfurther purified by MDAP (2×1 mL injection, formic). The requiredfractions from both injections were evaporated under a stream ofnitrogen, redissolved in methanol (approx. 2 mL each) anddichloromethane (approx. 2 mL each) and combined. This solution wasevaporated under a stream of nitrogen and the residue dried in vacuo togive a light yellow oily solid. This was further purified byredissolving the sample in dichloromethane (approx. 3 mL) and directlyapplying it to the top of a 10 g SNAP cartridge to be purified by SP4flash column chromatography. The column was eluted with a gradient of0-50% ethyl acetate:ethanol (3:1) in cyclohexane. The required fractionswere combined and evaporated in vacuo to give a white solid;N⁵-cyclopropyl-N³-methyl-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2-dihydropyridine-3,5-dicarboxamide(54.7 mg, 0.14 mmol, 64% yield).

LCMS (2 min high pH) Rt=0.98 min, m/z=394 for [MH]⁺

Example 319:(+/−)-1-((1H-Indol-4-yl)methyl)-N⁵-((trans)-2-(2-((2-acetamidoethyl)(methyl)amino)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-1-((1H-Indol-4-yl)methyl)-N-((trans)-2-(2-((2-aminoethyl)(methyl)amino)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(36.2 mg, 0.08 mmol) was taken up in DCM (5 mL). Et₃N (0.022 mL, 0.16mmol) then AcCl (6.09 μl, 0.09 mmol) was added and the reaction stirredat rt overnight. The reaction was concentrated in vacuo and purified byMDAP (high pH). The appropriate fractions were concentrated in vacuo togive(+/−)-1-((1H-indol-4-yl)methyl)-N⁵-((trans)-2-(2-((2-acetamidoethyl)(methyl)amino)ethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(9.7 mg, 0.02 mmol, 23% yield) as a cream solid.

LCMS (2 min High pH): Rt=0.79 min, [MH]⁺=507.4.

Example 320:1-Benzyl-N³-methyl-N⁵-((1R*,2R′-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideExample 321:1-Benzyl-N³-methyl-N⁵-((1S*,2S*)-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-1-Benzyl-N³-methyl-N⁵-((trans)-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(80 mg) was purified by chiral HPLC. The racemate was dissolved in EtOH(2 mL) with heat. Injection: 1 mL of the solution was injected onto thecolumn (15% EtOH (+0.2% isopropylamine)/heptane (+0.2% isopropylamine),flow rate=30 mL/min, detection wavelength=215 nm, 4. Ref 550, 100,Column 30 mm×25 cm Chiralcel OJ-H (5 μm), lot no. OJH10027-01). Totalnumber of injections=2. Fractions from 21-25 min were bulked andlabelled peak 1. Fractions from 29-34 min were bulked and labelled peak2. The bulked fractions were concentrated in vacuo and then transferredto weighed flasks. The final compounds were recovered from DCM andheptane in order to obtain a solid.

The fractions corresponding to peak 1 were collected to afford1-benzyl-N³-methyl-N⁵-((1R*,2R*)-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(24 mg, 0.06 mmol as a single unknown enantiomer (example 320).

LCMS (2 min Formic): Rt=0.58 min, [MH]⁺=439.4.

The fractions corresponding to peak 2 were collected to afford1-benzyl-N³-methyl-N⁵-((1S*,2S*)-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(25 mg, 0.06 mmol) as a single unknown enantiomer (example 321).

LCMS (2 min Formic): Rt=0.58 min, [MH]⁺=439.4.

Example 322:(+/−)-1-Benzyl-N³-methyl-N⁵-((trans)-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

(+/−)-1-Benzyl-N⁵-((trans)-2-(2-hydroxyethyl)cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(100 mg, 0.27 mmol) was suspended in DCM (5 mL), then Dess-Martinperiodinane (230 mg, 0.54 mmol) was added and the mixture was stirredovernight at rt, then washed with water and the organic layer dried andevaporated in vacuo to give a colourless gummy solid. The crude productwas suspended in DCM (5 mL) and morpholine (0.047 ml, 0.541 mmol) wasadded, followed by sodium triacetoxyborohydride (287 mg, 1.353 mmol).The mixture was stirred for 2 h, then washed with saturated sodiumbicarbonate solution, then the organic layer was dried and evaporated invacuo and the residue purified by MDAP (High pH) to give(+/−)-1-benzyl-N³-methyl-N⁵-((trans)-2-(2-morpholinoethyl)cyclopropyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(80 mg, 0.18 mmol, 67% yield)

LCMS (2 min High pH): Rt=0.88 min, [MH]⁺=439.4.

Example 323:1-Benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

2,4,6-Trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1g, 2.15 mmol) was taken up in THF (25 mL) and ammonia (21.47 mL, 10.74mmol) was added. The reaction was heated to 50° C. overnight. A thickprecipitate formed. The reaction mixture was cooled and partitionedbetween EtOAc and sat. NaHCO₃ (50 mL each). The aqueous phase wasre-extracted with EtOAc (2×50 mL) and the combined organics were elutedthrough a hydrophobic frit then concentrated in vacuo to give a whitesemi-solid. The crude product was taken up in the minimum volume of 20%MeOH in DCM and silica (˜2 g) added. The solvent was removed in vacuoand the silica was applied to a 25 g SNAP cartridge and was purified byflash chromatography, eluting with 10-100% (3:1 EtOAc:EtOH) incyclohexane. The appropriate fractions were concentrated in vacuo togive 1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (128mg, 0.43 mmol, 20% yield) as a cream solid.

Due to the poor recovery, the experiment was repeated.2,4,6-trichlorophenyl1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1g, 2.15 mmol) was taken up in THF (25 mL) and ammonia (21.47 mL, 10.74mmol) was added. The reaction was stirred at 50° C. for 5 h in total.The reaction was then cooled and filtered. The filter cake was washedwith EtOAc (5 mL) and dried in the vacuum oven over the weekend to give1-benzyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (562 mg,1.87 mmol, 87% yield) as a white solid.

LCMS (2 min High pH): Rt=0.74 min, [MH]⁺=286.3.

Example 324:(R*)—N⁵-Cyclopropyl-1-(2-hydroxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamideExample 325:(S*)—N⁵-Cyclopropyl-1-(2-hydroxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a flask containingN⁵-cyclopropyl-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(100 mg, 0.43 mmol) in trifluoroethanol (4 mL) was added 2-phenyloxirane(0.06 mL, 0.553 mmol, commercially available from, for example,Sigma-Aldrich) at rt. The reaction was heated to 75° C. and stirred for1 h at rt. The reaction was then heated for a further 16 h. The reactionmixture was concentrated in vacuo, and the crude starting material wasredissolved in ethanol (4 mL) and pyridine (0.069 mL, 0.85 mmol)followed by further 2-phenyloxirane (0.063 mL, 0.55 mmol) were added andthe reaction heated to reflux for 2 h. The reaction mixture was allowedto cool to rt and concentrated in vacuo to afford the crude product as adark oil. This was taken up in DCM and purified by flash SP4chromatography (10 g SNAP silica cartridge) eluting with 0-40% (25%EtOH/EtOAc)/cyclohexane. The product containing fractions were collectedtogether and concentrated in vacuo to afford the crude product as anorange foam. NMR showed the presence of two products in an 80:20 ratio,with the major component assigned as the undesired secondary alcohol:(+/−)-N⁵-cyclopropyl-1-(2-hydroxy-2-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide)with the desired product:(+/−)-N⁵-cyclopropyl-1-(2-hydroxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide)as the minor component.

The crude product was purified by chiral HPLC. The crude product (120mg) was dissolved in EtOH (3 mL). Injection: 1 mL of the solution wasinjected onto the column (40% EtOH (+0.2% isopropylamine)/heptane (+0.2%isopropylamine), flow rate=30 mL/min, detection wavelength=215 nm, 4.Ref 550, 100, Column 30 mm×25 cm Chiralcel IC (5 μm), lot no.IC10028-01). Total number of injections=3. Fractions from 12.5-14 minwere bulked and labelled peak 1. Fractions from 15-16 min were bulkedand labelled peak 2—this required a further chiral purification usingthe same method. Fractions from 18.5-21 min were bulked and labelledpeak 3. Fractions from 29-31.5 min were bulked and labelled peak 4. Thebulked fractions were concentrated in vacuo and then transferred toweighed flasks. The final compounds were recovered from DCM and heptanein order to obtain a solid.

Peaks 1 and 3 were confirmed as corresponding to both enantiomers of theundesired regioisomeric alcohol.

The fractions corresponding to peak 2 were collected to afford: Example324—(R*)—N⁵-cyclopropyl-1-(2-hydroxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(6 mg, 0.02 mmol, 4% yield)

LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=356.3.

The fractions corresponding to peak 4 were collected to afford: Example325—(S*)—N⁵-cyclopropyl-1-(2-hydroxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(8 mg, 0.02 mmol, 5% yield)

LCMS (2 min Formic): Rt=0.74 min, [MH]⁺=356.3.

Example 326:(S*)—N⁵-Cyclopropyl-1-(2-methoxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide

To a solution of(S*)—N⁵-cyclopropyl-1-(2-hydroxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(4.5 mg, 0.01 mmol) in DCM (1 mL) at rt was added Proton Sponge (27.1mg, 0.13 mmol), followed by Meerwein's salt (9.4 mg, 0.06 mmol). Thereaction was stirred for 2 h. Further Proton Sponge (27.1 mg, 0.13 mmol)and Meerwein's salt (9.4 mg, 0.06 mmol) were added and the reactionstirred overnight, during which time the DCM evaporated. Further DCM (1mL) was added. The reaction was stirred for a further 2 h. FurtherProton Sponge (27.1 mg, 0.13 mmol) and Meerwein's salt (9.4 mg, 0.06mmol) were added and the reaction stirred for a further 4 h and thenover the weekend, during which time the DCM evaporated. The reaction wasdiluted with DCM and quenched with sat. aq. NaHCO₃ solution (10 mL) anddiluted with DCM (10 mL). The layers were separated and the aqueouslayer was extracted with further DCM (2×10 mL). The combined organicswere dried and concentrated in vacuo. In order to remove the protonsponge the crude product was taken up in MeOH (20 mL) and added to apreconditioned SCX cartridge (1 g). The product was eluted from thiscolumn using MeOH with the proton sponge retained. The MeOH fractionswere concentrated in vacuo to afford the crude product. The crudeproduct was purified by SNAP (10 g cartridge) SP4 silica chromatographyeluting with 40% EtOAc/cyclohexane. The fractions were left overnight toallow partial evaporation and the appropriate fractions were thenconcentrated in vacuo to afford the desired product as a yellowoil—(S*)—N⁵-cyclopropyl-1-(2-methoxy-1-phenylethyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide(2.0 mg, 5.41 μmol, 43% yield)

LCMS (2 min Formic): Rt=0.88 min, [MH]⁺=370.2.

Examples 327-341

Examples 324-341 were prepared in an analogous manner to the previousexamples

Ex Rt No. Name Structure [MH]⁺ (min)* 327 N⁵-Cyclopropyl-N³-methyl-1-((2-methylbenzo[d]oxazol-7- yl)methyl)-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide

381.2 (formic) 0.73 328 1-((R*)-1-(3- Methoxyphenyl)ethyl)-N³-methyl-N⁵-((1S,2S)-2- methylcyclopropyl)-2-oxo- 1,2-dihydropyridine-3,5-dicarboxamide

384.2 (formic) 0.97 329 (+/−)-1-Benzyl-N⁵-((trans)- 2-((dimethylamino)methyl) cyclopropyl)-N³-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide

383.2 (formic) 0.52 330 1-((1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)-N⁵-cyclopropyl- N³-methyl-2-oxo-1,2- dihydropyridine-3,5-dicarboxamide, hydrochloride

366.3 (formic) 0.36 331 1-((6-Methoxypyridin-2- yl)methyl)-N³-methyl-N⁵-((1S,2S)-2- methylcyclopropyl)-2-oxo- 1,2-dihydropyridine-3,5-dicarboxamide

371.3 (formic) 0.86 332 N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1- (1-(pyridin-2-yl)ethyl)-1,2-dihydropyridine-3,5- dicarboxamide, 1:1 mixture of diastereomers atundefined stereocentre

355.2 (formic) 0.75 333 N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-2-oxo-1- (pyridin-2-ylmethyl)-1,2-dihydropyridine-3,5- dicarboxamide

341.2 (formic) 0.65 334 1-((4-Methoxypyridin-2- yl)methyl)-N³-methyl-N⁵-((1S,2S)-2- methylcyclopropyl)-2-oxo- 1,2-dihydropyridine-3,5-dicarboxamide

371.3 (formic) 0.51 335 N³-Methyl-N⁵-((1S,2S)-2-methylcyclopropyl)-1-((4- methylpyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridine- 3,5-dicarboxamide

355.3 (formic) 0.63 336 1-Benzyl-N⁵-((1R,2S)-2- ((dimethylamino)methyl)cyclopropyl)-N³-methyl-2-oxo- 1,2-dihydropyridine-3,5- dicarboxamide,formic acid salt

383.5 (formic) 0.52 337 1-(3,5-Dimethoxybenzyl)-N³-methyl-N⁵-((1S,2S)-2- methylcyclopropyl)-2-oxo- 1,2-dihydropyridine-3,5-dicarboxamide

400.4 (formic) 0.93 338 Methyl 4-((3- (methylcarbamoyl)-5- (((1S,2S)-2-methylcyclopropyl) carbamoyl)- 2-oxopyridin-1(2H)- yl)methyl)benzoate

398.4 (high pH) 0.93 339 4-((3-(Methylcarbamoyl)-5- (((1S,2S)-2-methylcyclopropyl) carbamoyl)- 2-oxopyridin-1(2H)- yl)methyl)benzoicacid

384.3 (high pH) 0.56 340 1-(4-(2- Aminoethoxy)benzyl)-N³-methyl-N⁵-((1S,2S)-2- methylcyclopropyl)-2-oxo- 1,2-dihydropyridine-3,5-dicarboxamide, hydrochloride

399.4 (high pH) 0.77 341 1-Benzyl-N⁵-((trans)-3- hydroxycyclobutyl)-N³-methyl-2-oxo-1,2- dihydropyridine-3,5- dicarboxamide

356.3 (formic) 0.73Biological Data

The compounds of formula (I) may be tested in one or more of thefollowing assays:

Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay

Bromodomain binding was assessed utilising a time resolved fluorescentresonance energy transfer (TR-FRET) competition assay. To enable thisapproach a known, high affinity, pan-BET interacting small molecule waslabelled with Alexa Fluor® 647, which is a far-red-fluorescent dye(Reference Compound X). Reference Compound X acts as a reporter ofbromodomain binding and is the acceptor fluorophore component of theTR-FRET pair. Europium chelate, conjugated to an anti-6*His antibody,was utilised as the donor fluorophore in the TR-FRET pair. Theanti-6*His antibody binds selectively to a six Histidine purificationepitope added to the amino-terminus of each of the BET tandembromodomain protein constructs used in this study. A TR-FRET signal isgenerated when the donor and acceptor fluorophores are in closeproximity, between 20-80 Å, which is enabled in this assay by binding ofReference Compound X to the bromodomain protein.

Reference Compound X:4-((Z)-3-(6-((5-(2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamido)pentyl)amino)-6-oxohexyl)-2-((2E,4E)-5-(3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-3H-indol-1-ium-2-yl)penta-2,4-dien-1-ylidene)-3-methyl-5-sulfoindolin-1-yl)butane-1-sulphonate)

To a solution ofN-(5-aminopentyl)-2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetamide(for a preparation see Reference Compound J, WO2011/054848A1, 1.7 mg,3.53 μmol) in DMF (40 μl) was added a solution of AlexaFluor647-ONSu(2.16 mg, 1.966 μmol) also in DMF (100 μl). The mixture was basifiedwith DIPEA (1 μl, 5.73 μmol) and agitated overnight on a vortex mixer.

The reaction mixture was evaporated to dryness. The solid was dissolvedin acetonitrile/water/acetic acid (5/4/1, <1 ml) filtered and wasapplied to a Phenomenex Jupiter C18 preparative column and eluted withthe following gradient (A=0.1% trifluoroacetic acid in water, B=0.1%TFA/90% acetonitrile/10% water): Flow rate=10 ml/min., AU=20/10 (214nm):

5-35%, t=0 min: B=5%; t=10 min: B=5%; t=100 min: B=35%; t=115 min:B=100% (Sep. grad: 0.33%/min)

The major component was eluted over the range 26-28% B but appeared tobe composed of two peaks. The middle fraction (F1.26) which shouldcontain “both” components was analysed by analytical HPLC (SpherisorbODS2, 1 to 35% over 60 min): single component eluting at 28% B.

Fractions F1.25/26&27 were combined and evaporated to dryness.Transferred with DMF, evaporated to dryness, triturated with dry etherand the blue solid dried overnight at <0.2 mbar: 1.54 mg.

Analytical HPLC (Sphersisorb ODS2, 1 to 35% B over 60 min): MSM10520-1:[M+H]⁺ (obs): 661.8/− corresponding with M-29. This equates to[(M+2H)/2]⁺ for a calculated mass of 1320.984 which is M-29. This is astandard occurrence with the Alexa Fluor 647 dye and represents atheoretical loss of two methylene groups under the conditions of themass spectrometer.

Assay Principle:

In order to generate a TR-FRET signal, donor fluorophore is excited by alaser at λ337 nm, which subsequently leads to emission at λ618 nm. Ifthe acceptor fluorophore is in close proximity then energy transfer canoccur, which leads to emission of Alexa Fluor® 647 at λ665 nm. In thepresence of competitor compound, Reference Compound X can be displacedfrom binding to the bromodomain. If displacement occurs, the acceptorfluorophore is no longer in proximity to the donor fluorophore, whichprevents fluorescent energy transfer and, subsequently, a loss of AlexaFluor® 647 emission at λ665 nm.

The competition of the compounds of formula (I) with Reference CompoundX for binding to the BET family (BRD2, BRD3, BRD4 and BRDT) was assessedusing protein truncates spanning both bromodomain 1 (BD1) andbromodomain 2 (BD2). In order to monitor differential binding to eitherBD1 or BD2, single residue mutations of key tyrosines to alanine weremade in the acetyl lysine binding pockets. To validate this approach, adouble residue mutant tandem domain protein was produced for each of theBET family members. Utilising a Fluorescence Polarisation approach,binding affinities for each of the single and double mutants forReference Compound X were determined. The affinities of the doublemutant tandem proteins for Reference Compound X were greatly greatlyreduced in comparison to the non mutated, wild type tandem BET proteins(>1000 fold reduction in Kd). The affinities of the single mutatedbromdomain tandem proteins for Reference Compound X were equi-potentwith the corresponding non-mutated BET protein. These data demonstratedthat single mutations of Tyrosine to Alanine reduce the Kd of theinteraction between the mutated bromodomain and Reference Compound Xby >1000 fold. In the TR-FRET competition assay, Reference Compound X isused at a concentration that is equivalent to the Kd for the non-mutatedbromodomain, which ensures that no binding at the mutated bromodomain isdetected.

Protein Production:

Recombinant Human Bromodomains [(BRD2 (1-473) (Y113A) and (Y386A), BRD3(1-435) (Y73A) and (Y348A) BRD4 (1-477) (Y97A) and (Y390A) and BRDT(1-397) (Y66A) and (Y309A)] were expressed in E. coli cells (in pET15bvector for BRD2/3/4 and in pET28a vector for BRDT) with a 6-His tag atthe N-terminal. The His-tagged Bromodomain pellet was resuspended in 50mM HEPES (pH7.5), 300 mM NaCl, 10 mM imidazole & 1 μl/ml proteaseinhibitor cocktail and extracted from the E. coli cells using sonicationand purified using a nickel sepharose high performance column, theproteins were washed and then eluted with a linear gradient of 0-500 mMimidazole with buffer 50 mM HEPES (pH7.5), 150 mM NaCl, 500 mMimidazole, over 20 column volumes. Final purification was completed bySuperdex 200 prep grade size exclusion column. Purified protein wasstored at −80° C. in 20 mM HEPES pH 7.5 and 100 mM NaCl. Proteinidentity was confirmed by peptide mass fingerprinting and predictedmolecular weight confirmed by mass spectrometry.

Protocol for Bromodomain BRD2, 3, 4 and T, BD1+BD2 Mutant TR-FRETCompetition Assays:

All assay components were dissolved in an assay buffer composing of 50mM HEPES pH7.4, 50 mM NaCl, 5% Glycerol, 1 mM DTT and 1 mM CHAPS.Reference Compound X was diluted, in assay buffer containing 20 nMsingle mutant, tandem bromodomain protein, to a concentration equivalentto 2*Kd for this bromodomain. The solution containing bromodomain andReference Compound X was added to dose response dilutions of testcompound or DMSO vehicle (a maximum of 0.5% DMSO is used in this assay)in Greiner 384 well black low volume microtitre plates and subsequentlyincubated for 30 minutes at room temperature. An equal volume of 3 nM ofanti-6*His Europium chelate was added to all wells, followed by afurther 30 minute incubation at room temperature. TR-FRET was detectedusing a Perkin Elmer Multimode plate reader, by exciting the donorfluorophore at λ337 nm and subsequently, after a delay of 50 μsecs,measuring emission of the donor and acceptor fluorophores at A615 nm andA665 nm, respectively. In order to control these assays, 16 replicateseach of uninhibited (DMSO vehicle) and inhibited (10*IC₅₀ concentrationsof Example 11 of WO 2011/054846A1) TR-FRET assays were included on everymicrotitre plate.

cA four parameter curve fit of the following form was then applied:y=a+((b−a)/(1+(10{circumflex over ( )}x/10{circumflex over( )}c){circumflex over ( )}d)

-   -   Where ‘a’ is the minimum, ‘b’ is the Hill slope, ‘c’ is the        pIC₅₀ and ‘d is the maximum.

All compounds (Examples 1-341) were each tested in the BRD4 BD1 and theBRD4 BD2 TR-FRET assays essentially as described above. Those of skillin the art will recognise that in vitro binding assays and cell-basedassays for functional activity are subject to experimental variability.Accordingly, it is to be understood that the pIC₅₀ values given beloware exemplary only. pIC₅₀ values are expressed as log₁₀ units.

All tested compounds were found to have a pIC₅₀≥4.0 in at least oneassay described above.

Examples 159, 160, 163, 168, 169, 171, 173, 177-180, 185, 186, 190, 194,196, 198-201, 206, 208, 211, 213, 214, 217, 219, 222, 243, 248, 250,267, 268, 324, 334, 335 and 339 were found to have a pIC₅₀≥4.0 and <6.0in the BRD4 BD2 assay.

All other tested compounds were found to have a pIC₅₀≥6.0 in the BRD4BD2 assay.

Example 1 had a mean pIC₅₀ of 7.1 (n=13) in the the BRD4 BD2 TR-FRETassay described above, and a mean pIC₅₀ of 4.8 (n=11) in the BRD4 BD1TR-FRET assay described above.

Example 102 had a mean pIC₅₀ of 7.6 (n=17) in the the BRD4 BD2 TR-FRETassay described above, and a mean pIC₅₀ of 5.1 (n=17) in the BRD4 BD1TR-FRET assay described above.

Example 153 had a mean pIC₅₀ of 7.2 (n=9) in the the BRD4 BD2 TR-FRETassay described above, and a mean pIC₅₀ of 4.5 (n=10) in the BRD4 BD1TR-FRET assay described above.

Calculation of Selectivity for BRD4 BD2 Over BRD4 BD1

Selectivity for BRD4 BD2 over BRD4 BD1 was calculated as follows:Selectivity=BRD4BD2pIC₅₀−BRD4BD1pIC₅₀

Examples 1-167, 170-172, 174-184, 186-207, 209-213, 215-267 and 269-341were found to have selectivity for BRD4 BD2 over BRD4 BD1 of ≥1 log unitin at least one of the TR-FRET assays described above, and hence are atleast 10 fold selective for BRD4 BD2 over BRD4 BD1.

Examples 1-156, 215, 221, 223, 224, 228, 229, 231-236, 238-242, 244-247,249, 251-266 and 269-321 were found to have selectivity for BRD4 BD2over BRD4 BD1 of ≥2 log unit in at least one of the TR-FRET assaysdescribed above, and hence are at least 100 fold selective for BRD4 BD2over BRD4 BD1.

Example 1 was found to have selectivity for BRD4 BD2 over BRD4 BD1 of2.4 log units in at least one of the TR-FRET assays described above, andhence is at least 100-fold selective for BRD4 BD2 over BRD4 BD1.

Example 102 was found to have a selectivity for BRD4 BD2 over BRD4 BD1of 2.5 log units in at least one of the TR-FRET assays described above,and hence is at least 100-fold selective for BRD4 BD2 over BRD4 BD1.

Example 153 was found to have a selectivity for BRD4 BD2 over BRD4 BD1of 2.7 log units in at least one of the TR-FRET assays described above,and hence is at least 100-fold selective for BRD4 BD2 over BRD4 BD1.

The invention claimed is:
 1. A pharmaceutical composition comprising acompound which is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 2. The pharmaceutical composition according toclaim 1, wherein the composition is suitable for oral administration. 3.The pharmaceutical composition according to claim 2 in the form of atablet.
 4. The pharmaceutical composition according to claim 2 in theform of a capsule.
 5. A pharmaceutical composition comprising a compoundwhich is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 6. The pharmaceutical composition according toclaim 5, wherein the composition is suitable for oral administration. 7.The pharmaceutical composition according to claim 6 in the form of atablet.
 8. The pharmaceutical composition according to claim 6 in theform of a capsule.